Sustained release compositions of 4-aminopyridine

ABSTRACT

The present invention generally relates to sustained release 4-aminopyridine tablets, which include a core and a coating. The sustained release tablets of the invention are generally suitable for once daily oral administration for the treatment of neurological disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/234,455, filed Sep. 29, 2015, which is incorporatedby reference herein in its entirety.

1 FIELD OF THE INVENTION

The present invention generally relates to sustained release4-aminopyridine tablets, which include a core and a coating. Thesustained release tablets of the invention are generally suitable foronce daily oral administration for the treatment of neurologicaldisorders.

2 BACKGROUND OF THE INVENTION

4-Aminopyridine is a potassium (K+) channel blocker approved by the U.S.Food and Drug Administration as a treatment for patients with multiplesclerosis to improve walking. Dalfampridine is the United States AdoptedName (USAN) for the chemical 4-aminopyridine, which has a molecularformula of C₅H₆N₂ and molecular weight of 94.1; the former USAN name forthis compound was fampridine (which remains the InternationalNonproprietary Name). The terms “dalfampridine”, “fampridine” and“4-aminopyridine” will be used throughout this specification to refer tothe active drug substance.

Studies of 4-aminopyridine (dalfampridine, fampridine) have beenconducted using intravenous (i.v.) administration and immediate-release(IR) oral capsule formulations in addition to controlled-release orsustained-release formulations. Administration of IR capsules resultedin rapid and short-lasting peaks of 4-aminopyridine in the plasma. Earlypharmacokinetic studies were conducted using an immediate release (IR)formulation for oral administration, which consisted of 4-aminopyridinepowder in a gelatin-based capsule or oral solution. Administrationresulted in rapidly changing 4-aminopyridine plasma levels that were notwell tolerated. A sustained-release matrix tablet (known asFampridine-SR or AMPYRA®, Acorda Therapeutics, Ardsley, N.Y.) was thendeveloped. The sustained release matrix tablet showed improved stabilityand an appropriate pharmacokinetic profile for twice-daily dosing.Sustained release compositions of 4-aminopyridine and related use ofsuch compositions are set forth, e.g., in U.S. Pat. Nos. 5,370,879;5,540,938; 8,007,826; 8,354,437; 8,663,655; International Publication WO2012/10347, and International Publication WO 2014/093475. For example,suitable formulations, methods of manufacture, pharmacokineticcharacteristics of sustained release aminopyridine compositions andmethods of treating various neurological disorders are further describedin U.S. Pat. No. 8,007,826 entitled “Sustained Release AminopyridineComposition” issued on Aug. 30, 2011; and U.S. Pat. No. 8,354,437entitled “Methods of Using Sustained Release Aminopyridine Compositions”issued on Jan. 15, 2013.

Provided herein are once daily sustained release 4-aminopyridine tabletsthat deliver a therapeutically effective amount of the active agent over24 hours for the treatment of neurological disorders.

3 SUMMARY OF THE INVENTION

Provided herein is a sustained release tablet comprising:

(a) a compressed core, said compressed core comprising 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 10% w/w of the compressed core.

Provided herein is a sustained release tablet comprising:

(a) a compressed core, said compressed core comprising 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, wherein the ratio of the amount of the ethylcellulose coat to theamount of 4-aminopyridine in the compressed core is in the range ofabout 0.5:1 to about 3:1; wherein for calculating said ratio, the amountof the ethylcellulose coat is the weight percentage of theethylcellulose coat by weight of the compressed core, and the amount of4-aminopyridine is the weight percentage of 4-aminopyridine by weight ofthe compressed core.

Provided herein is a sustained release tablet comprising:

(a) a compressed core, said compressed core comprising 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, wherein the ratio of the amount of the ethylcellulose coat to theamount of 4-aminopyridine in the compressed core is in the range ofabout 0.1:1 to about 0.7:1; wherein for calculating said ratio, theamount of the ethylcellulose coat is the weight percentage of theethylcellulose coat by weight of the compressed core, and the amount of4-aminopyridine is the weight in milligrams of 4-aminopyridine.

In one embodiment, the sustained release tablet provided herein is theproduct of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises heating the coated compressed core to a temperature above 23°C. for a period of time of at least 15 minutes.

In one embodiment of the sustained release tablet provided herein, thecuring step comprises exposing the coated compressed core to atemperature in the range of 40−70° C. for a period of time of at least 1hour.

In one embodiment of the sustained release tablet provided herein, thecuring step comprises exposing the coated compressed core to atemperature in the range of 50-60° C. for a period of time of at least 1hour.

Provided herein is a sustained release tablet comprising:

(a) a compressed core, said compressed core comprising 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about8% w/w to about 10% w/w of the tablet, wherein said tablet is theproduct of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises heating the coated compressed core to a temperature above 23°C. for a period of time of at least 15 minutes.

In one embodiment of the sustained release tablet provided herein, themixture comprising polyvinyl acetate and polyvinyl pyrrolidone furthercomprises one or more pharmaceutically acceptable excipients.

In one embodiment of the sustained release tablet provided herein, themixture comprising polyvinyl acetate and polyvinyl pyrrolidone comprises70-90% polyvinyl acetate and 15-20% polyvinyl pyrrolidone.

In one embodiment of the sustained release tablet provided herein, themixture comprising polyvinyl acetate and polyvinyl pyrrolidone furthercomprises a surfactant.

In one embodiment of the sustained release tablet provided herein, themixture comprising polyvinyl acetate and polyvinyl pyrrolidone furthercomprises silica.

In one embodiment of the sustained release tablet provided herein, themixture comprising polyvinyl acetate and polyvinyl pyrrolidone consistsof about 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about0.8% sodium lauryl sulfate, and about 0.2% silica.

In one embodiment of the sustained release tablet provided herein, thecompressed core comprising 4-aminopyridine further comprises a fillerand a lubricant. In one embodiment, the filler is dibasic calciumphosphate dihydrate, and the lubricant is magnesium stearate.

In one aspect, provided herein is a sustained release tablet comprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, (ii) a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000, (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica, (iv) dibasic calciumphosphate dihydrate, and (v) magnesium stearate; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 10% w/w of the compressed core, wherein the amount of4-aminopyridine is in the range of about 4% w/w to about 6% w/w of thecompressed core.

In one embodiment of the sustained release tablet provided herein, theamount of the ethylcellulose coat surrounding the compressed core isabout 9% w/w of the compressed core.

In one aspect, provided herein is a sustained release tablet comprising:

(a) a compressed core, said compressed core comprising 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 7% w/w of the compressed core.

In one embodiment of the sustained release tablet provided herein, theamount of 4-aminopyridine is in the range of about 3% w/w to about 5%w/w of the compressed core and the amount of the ethylcellulose coatsurrounding the compressed core is about 6% w/w of the compressed core.

In one aspect, provided herein is a sustained release tablet comprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, (ii) a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000, (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica, (iv) dibasic calciumphosphate dihydrate, and (v) magnesium stearate; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about8% w/w to about 10% w/w of the tablet, wherein said sustained releasetablet is the product of a process comprising a curing step aftercoating the compressed core with ethylcellulose, wherein said curingstep comprises exposing the coated compressed core to a temperature inthe range of 50-60° C. for a period of time of at least 1 hour, andwherein the amount of 4-aminopyridine is in the range of about 4% w/w toabout 6% w/w of the sustained release tablet.

In one embodiment, the polyethylene oxide in the sustained releasetablet provided herein has a molecular weight between 4,000,000 and8,000,000.

In one embodiment, the polyethylene oxide in the sustained releasetablet provided herein has a molecular weight of 7,000,000.

In one embodiment, the total amount of the 4-aminopyridine in the tabletprovided herein is in the range of about 1% w/w to about 10% w/w of thesustained release tablet.

In one embodiment, the total amount of the 4-aminopyridine in the tabletprovided herein is in the range of about 1% w/w to about 10% w/w of thecompressed core.

In one embodiment of the sustained release tablet provided herein, theamount of 4-aminopyridine in the compressed core is in the range ofabout 12 mg to about 25 mg.

In one embodiment of the sustained release tablet provided herein, theamount of 4-aminopyridine in the compressed core is in the range ofabout 20 mg to about 25 mg.

In one embodiment of the sustained release tablet provided herein, theamount of 4-aminopyridine in the compressed core is about 22 mg.

In one embodiment of the sustained release tablet provided herein, theamount of 4-aminopyridine in the compressed core is about 16.5 mg.

In one embodiment of the sustained release tablet provided herein, theamount of 4-aminopyridine in the compressed core is in the range ofabout 5 mg to about 12 mg.

In one aspect, provided herein is a sustained release tablet comprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, wherein the amount of the polyethylene oxide is in the rangeof about 10% w/w to about 20% w/w of the compressed core; (iii) amixture consisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is in the range of about 20% w/w toabout 30% w/w of the compressed core; (iv) dibasic calcium phosphatedihydrate, wherein the amount of dibasic calcium phosphate dihydrate isin the range of about 50% w/w to about 60% w/w of the compressed core;and (v) magnesium stearate, wherein the amount of magnesium stearate isin the range of about 0.7% w/w to about 1.3% w/w of the compressed core;and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 10% w/w of the compressed core.

In one aspect, provided herein is a sustained release tablet comprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 54% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core;

and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 9% w/w of thecompressed core.

In one embodiment of the foregoing, the amount of 4-aminopyridine in thecompressed core is about 22 mg.

In one aspect, provided herein is a sustained release tablet comprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 3% w/w to about 5% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, wherein the amount of the polyethylene oxide is in the rangeof about 10% w/w to about 20% w/w of the compressed core; (iii) amixture consisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is in the range of about 20% w/w toabout 30% w/w of the compressed core; (iv) dibasic calcium phosphatedihydrate, wherein the amount of dibasic calcium phosphate dihydrate isin the range of about 50% w/w to about 60% w/w of the compressed core;and (v) magnesium stearate, wherein the amount of magnesium stearate isin the range of about 0.7% w/w to about 1.3% w/w of the compressed core;and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 7% w/w of the compressed core.

In one aspect, provided herein is a sustained release tablet comprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 3% w/w to about 5% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 55% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core;

and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 6% w/w of thecompressed core.

In one embodiment of the foregoing, the amount of 4-aminopyridine in thecompressed core is about 16.5 mg.

In one embodiment, the sustained release tablet provided herein does notfurther comprise an immediate release drug overcoat containing4-aminopyridine.

In one embodiment, the sustained release tablet provided herein providesa zero-order or near-zero-order release of the 4-aminopyridine. In oneembodiment, the release is zero-order.

In one embodiment, the sustained release tablet provided herein issuitable for once daily oral administration.

In one embodiment, the sustained release tablet provided hereincomprises an amount of 4-aminopyridine that is therapeutically effectiveover a period of 24 hours upon oral administration to a human patient.

In one embodiment, the release of the 4-aminopyridine from the sustainedrelease tablet provided herein, upon subjecting the tablet to an invitro dissolution test employing 50 mM Phosphate Buffer, pH 6.8 asdissolution medium, is as follows:

within the first 2 hours after the start of the test at most 30% w/w ofthe total amount of the 4-aminopyridine contained in the sustainedrelease tablet is released.

In one embodiment, the release of the 4-aminopyridine from the sustainedrelease tablet provided herein, upon subjecting the tablet to an invitro dissolution test employing 50 mM Phosphate Buffer, pH 6.8 asdissolution medium, is as follows:

(a) within the first 2 hours after the start of the test at most 30% w/wof the total amount of the 4-aminopyridine contained in the sustainedrelease tablet is released, and

(b) within the first 24 hours after the start of the test at least 80%w/w of the total amount of the 4-aminopyridine contained in thesustained release tablet is released.

In one embodiment, the release of the 4-aminopyridine from the sustainedrelease tablet provided herein, upon subjecting the tablet to an invitro dissolution test employing 50 mM Phosphate Buffer, pH 6.8 asdissolution medium, is as follows:

within the first 2 hours after the start of the test at most 20% w/w ofthe total amount of the 4-aminopyridine contained in the sustainedrelease tablet is released.

In one embodiment, the release of the 4-aminopyridine from the sustainedrelease tablet provided herein, upon subjecting the tablet to an invitro dissolution test employing 50 mM Phosphate Buffer, pH 6.8 asdissolution medium, is as follows:

(a) within the first 2 hours after the start of the test at most 20% w/wof the total amount of the 4-aminopyridine contained in the sustainedrelease tablet is released, and

(b) within the first 24 hours after the start of the test at least 80%w/w of the total amount of the 4-aminopyridine contained in thesustained release tablet is released.

In one embodiment, the sustained release tablet provided herein furthercomprises an immediate release drug overcoat containing 4-aminopyridine.

Provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (v) magnesiumstearate;

(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingin the range of about 5% w/w to about 10% w/w of the compressed core;and

(c) curing the coated compressed core by exposing it to a temperature inthe range of 40-70° C. for a period of time of at least 1 hour.

Provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (v) magnesiumstearate;

(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingin the range of about 8% w/w to about 10% w/w of the sustained releasetablet; and

(c) curing the coated compressed core by exposing it to a temperature inthe range of 40-70° C. for a period of time of at least 1 hour.

In one embodiment, forming the compressed core in the method of makingprovided herein comprises:

(a) blending the 4-aminopyridine, polyethylene oxide, the mixturecomprising polyvinyl acetate and polyvinyl pyrrolidone, and dibasiccalcium phosphate dihydrate to form a blended mixture;

(b) adding magnesium stearate to the blended mixture to form a newblend; and

(c) compressing the new blend to form a compressed core.

In one embodiment of the method of making provided herein, the mixturecomprising polyvinyl acetate and polyvinyl pyrrolidone consists of about80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% silica.

In one embodiment of the method of making provided herein, thepolyethylene oxide has a molecular weight between 4,000,000 and8,000,000. In one embodiment, the polyethylene oxide has a molecularweight of 7,000,000.

In one embodiment of the method of making provided herein, the coatingcomprises applying an aqueous ethylcellulose dispersion to thecompressed core.

In one embodiment of the method of making provided herein, the totalamount of the 4-aminopyridine in the sustained release tablet is in therange of about 1% w/w to about 10% w/w of the compressed core.

In one embodiment of the method of making provided herein, the totalamount of the 4-aminopyridine in the sustained release tablet is in therange of about 1% w/w to about 10% w/w of the sustained release tablet.

Provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, whereinthe amount of 4-aminopyridine is in the range of about 4% w/w to about6% w/w of the compressed core, (ii) a polyethylene oxide with amolecular weight of 7,000,000, wherein the amount of the polyethyleneoxide is about 15% w/w of the compressed core, (iii) a mixtureconsisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is about 25% w/w of the compressedcore; (iv) dibasic calcium phosphate dihydrate, wherein the amount ofdibasic calcium phosphate dihydrate is about 54% w/w of the compressedcore; and (v) magnesium stearate, wherein the amount of magnesiumstearate is about 1% w/w of the compressed core;

(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingabout 9% w/w of the compressed core; and

(c) curing the coated compressed core by exposing it to a temperature inthe range of 50-60° C. for a period of time of at least 1 hour.

In one embodiment of the foregoing method of making, the amount of4-aminopyridine in the compressed core is about 22 mg.

Provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, whereinthe amount of 4-aminopyridine is in the range of about 3% w/w to about5% w/w of the compressed core, (ii) a polyethylene oxide with amolecular weight of 7,000,000, wherein the amount of the polyethyleneoxide is about 15% w/w of the compressed core, (iii) a mixtureconsisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is about 25% w/w of the compressedcore; (iv) dibasic calcium phosphate dihydrate, wherein the amount ofdibasic calcium phosphate dihydrate is about 55% w/w of the compressedcore; and (v) magnesium stearate, wherein the amount of magnesiumstearate is about 1% w/w of the compressed core;

(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingabout 6% w/w of the compressed core; and

(c) curing the coated compressed core by exposing it to a temperature inthe range of 50-60° C. for a period of time of at least 1 hour.

In one embodiment of the foregoing method of making, the amount of4-aminopyridine in the compressed core is about 16.5 mg.

In one embodiment of the method of making provided herein, the sustainedrelease tablet is suitable for once daily oral administration.

In one embodiment of the method of making provided herein, the sustainedrelease tablet comprises an amount of 4-aminopyridine that istherapeutically effective over a period of 24 hours.

Provided herein is a method of treating a neurological disorder in apatient in need thereof comprising orally administering to the patientonce daily the sustained release tablet provided herein.

Provided herein is a method of treating a neurological disorder in apatient in need thereof comprising orally administering to the patient atherapeutically effective amount of the sustained release tabletprovided herein, in combination with one or more additional medicaments.In one embodiment of the method of treating provided herein, theneurological disorder is multiple sclerosis, and the one or moreadditional medicaments is a therapeutic agent effective for thetreatment of multiple sclerosis. In one embodiment, the one or moretherapeutic agents effective for the treatment of multiple sclerosis isselected from the group consisting of interferon beta-1a, interferonbeta-1b, glatiramer acetate, mitoxantrone, natalizumab, teriflunomide,fingolimod, alemtuzumab, peginterferon beta-1a, dimethyl fumarate,prednisone, prednisolone, methylprednisolone, betamethasone, anddexamethasone.

In one embodiment of the method of treating provided herein, theneurological disorder is multiple sclerosis or stroke.

In one embodiment of the method of treating provided herein, theneurological disorder is multiple sclerosis.

In one embodiment of the method of treating provided herein, theneurological disorder is a walking impairment associated with multiplesclerosis.

In one embodiment of the method of treating provided herein, theneurological disorder is a neurocognitive or neuropsychiatric impairmentassociated with multiple sclerosis.

In one embodiment of the method of treating provided herein, theneurological disorder is stroke.

In one embodiment of the method of treating provided herein, theneurological disorder is a sensorimotor impairment associated withstroke.

In one embodiment of the method of treating provided herein, theneurological disorder is a walking impairment associated with stroke.

In one embodiment of the method of treating provided herein, the patientis a human patient.

4 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a dissolution profile of the sustained release tablet inExample 1 employing 50 mM Phosphate Buffer, pH 6.8 as a dissolutionmedium.

FIG. 2 depicts dissolution profiles of the sustained release tablet inExample 1 employing 0.1 N hydrochloric acid as a dissolution medium withand without 40% alcohol (ethanol).

FIG. 3 depicts dissolution profiles of sustained release tabletscontaining 22 mg 4-aminopyridine, coated to 8%, 9%, and 10% weight gain,employing 50 mM Phosphate Buffer, pH 6.8 as a dissolution medium.

FIG. 4 depicts dissolution profiles of sustained release tabletscontaining 16.5 mg 4-aminopyridine, coated to 5%, 6%, and 7% weightgain, employing 50 mM Phosphate Buffer, pH 6.8 as a dissolution medium.

FIG. 5 depicts a dissolution profile of the sustained release tablet inExample 4 employing 50 mM Phosphate Buffer, pH 6.8 as a dissolutionmedium.

FIG. 6 depicts mean plasma levels following administration of a singleoral dose of the 22 mg 4-aminopyridine sustained release tablet ofExample 1 in human subjects in fed and fasted states.

5 DETAILED DESCRIPTION

5.1 Sustained Release Tablets

The invention provides sustained release tablets comprising4-aminopyridine as the active ingredient, preferably for once dailyadministration.

Provided herein are sustained release tablets comprising: (a) acompressed core, said compressed core comprising 4-aminopyridine, apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and (b) an amount of an ethylcellulose coat surroundingsaid compressed core, wherein the ratio of the amount of theethylcellulose coat to the amount of 4-aminopyridine in the compressedcore is in the range of about 0.5:1 to about 3:1; wherein forcalculating said ratio, the amount of the ethylcellulose coat is theweight percentage of the ethylcellulose coat by weight of the compressedcore, and the amount of 4-aminopyridine is the weight percentage of4-aminopyridine by weight of the compressed core. In a specificembodiment of the foregoing, the sustained release tablet is the productof a process comprising a curing step after coating the compressed corewith ethylcellulose, and wherein said curing step comprises heating thecoated compressed core to a temperature above 23° C. for a period oftime of at least 15 minutes.

Also provided herein are sustained release tablets comprising: (a) acompressed core, said compressed core comprising 4-aminopyridine, apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and (b) an amount of an ethylcellulose coat surroundingsaid compressed core, wherein the ratio of the amount of theethylcellulose coat to the amount of 4-aminopyridine in the compressedcore is in the range of about 0.1:1 to about 0.7:1; wherein forcalculating said ratio, the amount of the ethylcellulose coat is theweight percentage of the ethylcellulose coat by weight of the compressedcore, and the amount of 4-aminopyridine is the weight in milligrams of4-aminopyridine. In a specific embodiment of the foregoing, thesustained release tablet is the product of a process comprising a curingstep after coating the compressed core with ethylcellulose, and whereinsaid curing step comprises heating the coated compressed core to atemperature above 23° C. for a period of time of at least 15 minutes.

Also provided herein are sustained release tablets comprising: (a) acompressed core, said compressed core comprising 4-aminopyridine, apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and (b) an amount of an ethylcellulose coat surroundingsaid compressed core, said amount of the ethylcellulose coat being inthe range of about 8% w/w to about 10% w/w of the tablet. In a specificembodiment of the foregoing, the sustained release tablet is the productof a process comprising a curing step after coating the compressed corewith ethylcellulose, and wherein said curing step comprises heating thecoated compressed core to a temperature above 23° C. for a period oftime of at least 15 minutes.

Also provided herein are sustained release tablets comprising: (a) acompressed core, said compressed core comprising 4-aminopyridine, apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and (b) an amount of an ethylcellulose coat surroundingsaid compressed core, said amount of the ethylcellulose coat being inthe range of about 5% w/w to about 10% w/w of the compressed core. In aspecific embodiment of the foregoing, the sustained release tablet isthe product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises heating the coated compressed core to a temperature above 23°C. for a period of time of at least 15 minutes.

Also provided herein are sustained release tablets comprising:

(a) a compressed core, wherein said compressed core comprises (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 54% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core;

and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 9% w/w of thecompressed core.

In a specific embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 22 mg. In anotherspecific embodiment of the foregoing, the sustained release tablet isthe product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

Also provided herein are sustained release tablets comprising:

(a) a compressed core, wherein said compressed core comprises (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 54% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 5% w/w of thecompressed core.

In a specific embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 22 mg. In anotherspecific embodiment of the foregoing, the sustained release tablet isthe product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

Also provided herein are sustained release tablets comprising: (a) acompressed core, said compressed core comprising 4-aminopyridine, apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and (b) an amount of an ethylcellulose coat surroundingsaid compressed core, said amount of the ethylcellulose coat being inthe range of about 5% w/w to about 7% w/w of the compressed core. In aspecific embodiment of the foregoing, the sustained release tablet isthe product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises heating the coated compressed core to a temperature above 23°C. for a period of time of at least 15 minutes.

Also provided herein are sustained release tablets comprising:

(a) a compressed core, wherein said compressed core comprises (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 3% w/w to about 5% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 55% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core;

and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 6% w/w of thecompressed core.

In a specific embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 16.5 mg. In anotherspecific embodiment of the foregoing, the sustained release tablet isthe product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

In specific embodiments, the sustained release tablets comprise, orconsist essentially of, or consist of, the components as describedherein. The sustained release tablets are pharmaceutically acceptable.The terms “sustained release” and “extended release” as used herein aregenerally synonymous unless the context clearly indicates otherwise.

In a specific embodiment, the compressed core provided herein comprises4-aminopyridine, a polyethylene oxide with a molecular weight betweenabout 1,000,000 and 10,000,000, and a mixture comprising polyvinylacetate and polyvinyl pyrrolidone. In a specific embodiment, thecompressed core provided herein consists essentially of 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone. In a specific embodiment, the mixture consists essentiallyof polyvinyl acetate and polyvinyl pyrrolidone, and optionally asurfactant and optionally silica.

In a specific embodiment, the amount of 4-aminopyridine in the sustainedrelease tablet is in the range of about 1% w/w to about 10% w/w of thesustained release tablet. In some embodiments, the amount of4-aminopyridine in the sustained release tablet is in range of about 1%w/w to about 7% w/w, about 1% w/w to about 5% w/w, about 1% w/w to about3% w/w, about 1% w/w to about 2% w/w, about 2% w/w to about 10% w/w,about 2% w/w to about 7% w/w, about 2% w/w to about 5% w/w, about 2% w/wto about 3% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 7%w/w, about 3% w/w to about 5% w/w, about 3% w/w to about 4% w/w, about4% w/w to about 10% w/w, about 4% w/w to about 7% w/w, about 4% w/w toabout 6% w/w, about 4% w/w to about 5% w/w, about 5% w/w to about 10%w/w, about 5% w/w to about 7% w/w, about 5% w/w to about 6% w/w, 7% w/wto about 10% w/w, about 7% w/w to about 8% w/w, about 7% w/w to about 9%w/w, about 8% w/w to about 10% w/w, about 8% w/w to about 9% w/w, orabout 9% w/w to about 10% w/w of the sustained release tablet.

In a specific embodiment, the amount of 4-aminopyridine in thecompressed core is in the range of about 1% w/w to about 10% w/w of thecompressed core. In some embodiments, the amount of 4-aminopyridine inthe compressed core is in range of about 1% w/w to about 7% w/w, about1% w/w to about 5% w/w, about 1% w/w to about 3% w/w, about 1% w/w toabout 2% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 7%w/w, about 2% w/w to about 5% w/w, about 2% w/w to about 3% w/w, about3% w/w to about 10% w/w, about 3% w/w to about 7% w/w, about 3% w/w toabout 5% w/w, about 3% w/w to about 4% w/w, about 4% w/w to about 10%w/w, about 4% w/w to about 7% w/w, about 4% w/w to about 6% w/w, about4% w/w to about 5% w/w, about 5% w/w to about 10% w/w, about 5% w/w toabout 7% w/w, about 5% w/w to about 6% w/w, 7% w/w to about 10% w/w,about 7% w/w to about 8% w/w, about 7% w/w to about 9% w/w, about 8% w/wto about 10% w/w, about 8% w/w to about 9% w/w, or about 9% w/w to about10% w/w of the compressed core. In some embodiments, the amount of4-aminopyridine in the compressed core is about 2% w/w, about 2.25% w/w,about 2.5% w/w, about 2.75% w/w, about 3% w/w, about 3.25% w/w, about3.5% w/w, about 3.75% w/w, about 4% w/w, about 4.25% w/w, about 4.5%w/w, about 4.75% w/w, or about 5% w/w of the compressed core. In aspecific embodiment, the amount of 4-aminopyridine in the compressedcore is in the range of about 3% w/w to about 5% of the compressed core.In another specific embodiment, the amount of 4-aminopyridine in thecompressed core is in the range of about 4% w/w to about 6% w/w of thecompressed core. In a specific embodiment, the amount of 4-aminopyridinein the compressed core is about 2.5% w/w of the compressed core. In aspecific embodiment, the amount of 4-aminopyridine in the compressedcore is about 3.75% w/w of the compressed core. In a specificembodiment, the amount of 4-aminopyridine in the compressed core isabout 5% w/w of the compressed core.

In some embodiments, the amount of 4-aminopyridine in the compressedcore is in the range of about 5 mg to about 40 mg. In some embodiments,the amount of 4-aminopyridine in the compressed core is in the range ofabout 5 mg to about 35 mg, about 5 mg to about 30 mg, about 5 mg toabout 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, about5 mg to about 10 mg, about 10 mg to about 40 mg, about 10 mg to about 35mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mgto about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 40 mg,about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg toabout 25 mg, about 15 mg to about 20 mg, about 20 mg to about 40 mg,about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg toabout 25 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg,about 25 mg to about 30 mg, about 30 mg to about 40 mg, about 30 mg toabout 35 mg, or about 35 mg to about 40 mg. In a specific embodiment,the amount of 4-aminopyridine in the compressed core is about 16 mg,about 16.2 mg, about 16.4 mg, about 16.6 mg, about 16.8 mg, about 17 mg,about 17.2 mg, about 17.4 mg, about 17.6 mg, about 17.8 mg, about 18 mg,about 18.2 mg, about 18.4 mg, about 18.6 mg, about 18.8 mg, about 19 mg,about 19.2 mg, about 19.4 mg, about 19.6 mg, about 19.8 mg, about 20 mg,about 20.2 mg, about 20.4 mg, about 20.6 mg, about 20.8 mg, about 21 mg,about 21.2 mg, about 21.4 mg, about 21.6 mg, about 21.8 mg, about 22 mg,about 22.2 mg, about 22.4 mg, about 22.6 mg, about 22.8 mg, about 23 mg,about 23.2 mg, about 23.4 mg, about 23.6 mg, about 23.8 mg, about 24 mg,about 24.2 mg, about 24.4 mg, about 24.6 mg, about 24.8 mg, or about 25mg. In one embodiment, the amount of 4-aminopyridine in the compressedcore is in the range of about 12 mg to about 40 mg. In one embodiment,the amount of 4-aminopyridine in the compressed core is in the range ofabout 12 mg to about 25 mg. In one embodiment, the amount of4-aminopyridine in the compressed core is in the range of about 12 mg toabout 15 mg. In one embodiment, the amount of 4-aminopyridine in thecompressed core is in the range of about 5 mg to about 12 mg. In aspecific embodiment, the amount of 4-aminopyridine in the compressedcore is about 22 mg. In another specific embodiment, the amount of4-aminopyridine in the compressed core is about 16.5 mg. In anotherspecific embodiment, the amount of 4-aminopyridine in the compressedcore is about 11 mg. In a preferred embodiment, 4-aminopyridine ispresent only in the compressed core (and thus the sustained releasetablet does not have an immediate-release drug overcoat containing4-aminopyridine). In an alternative specific embodiment, 4-aminopyridineis present only in: the compressed core and in an immediate-release drugovercoat of the sustained release tablet.

In a specific embodiment, the amount of 4-aminopyridine in thecompressed core is about 5% w/w of the compressed core, said amountbeing equal to about 22 mg. In another specific embodiment, the amountof 4-aminopyridine in the sustained release tablet is about 3.75% w/w ofthe compressed core, said amount being equal to about 16.5 mg.

The sustained release tablet provided herein comprises one or morepolymers that are capable of modifying the release rate of the4-aminopyridine from the sustained release tablet. Examples of suchrelease modifying polymers include, but are not limited to, polyethyleneoxide, a mixture of polyvinyl acetate and polyvinyl pyrrolidone (e.g.,KOLLIDON® SR), hypromellose, ethylcellulose, povidone, and anycombination thereof. In one embodiment, the sustained release tabletcomprises polyethylene oxide and a mixture of polyvinyl acetate andpolyvinyl pyrrolidone (e.g., KOLLIDON® SR).

Polyethylene oxide is a hydrophilic, water soluble polymer with goodbinding, thickening, lubricity, water retention, and film formingproperties. Polyethylene oxide also has beneficial effects in retardingthe release rate of a drug from a suitable pharmaceutical composition.In a specific embodiment, the polyethylene oxide present in thesustained release tablet disclosed herein has a molecular weight between4,000,000 and 8,000,000. In another specific embodiment, thepolyethylene oxide has a molecular weight of 7,000,000. In anotherspecific embodiment, the polyethylene oxide is sold under the namePOLYOX WSR-303 available from Dow Chemical Co.

In some embodiments, the amount of the polyethylene oxide in thecompressed core is in the range of about 5% w/w to about 25% w/w of thecompressed core. In some embodiments, the amount of the polyethyleneoxide in the compressed core is in the range of about 5% w/w to about20% w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w/w,about 10% w/w to about 25% w/w, 10% w/w to about 20% w/w, about 10% w/wto about 15% w/w, about 12% w/w to about 25% w/w, about 12% w/w to about20% w/w, about 12% w/w to about 15% w/w, about 15% w/w to about 25% w/w,15% w/w to about 20% w/w, or about 20% w/w to about 25% w/w of thecompressed core. In a specific embodiment, the amount of thepolyethylene oxide in the compressed core is about 10% w/w, about 10.5%w/w, about 11% w/w, about 11.5% w/w, about 12.5% w/w, about 13% w/w,about 13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about15.5% w/w, about 16% w/w, about 16.5% w/w, or about 17% w/w of thecompressed core. In a specific embodiment, the amount of thepolyethylene oxide in the compressed core is in the range of about 10%w/w to about 20% w/w of the compressed core. In a specific embodiment,the amount of the polyethylene oxide in the compressed core is about 15%w/w of the compressed core. In another specific embodiment, thepolyethylene oxide in the compressed core is a polyethylene oxide havinga molecular weight of about 7,000,000, which is present in an amount ofabout 15% w/w of the compressed core.

In a specific embodiment, the mixture of polyvinyl acetate and polyvinylpyrrolidone present in the sustained release tablet disclosed hereinfurther comprises a surfactant. In a specific embodiment, the mixturefurther comprises silica. In another specific embodiment, the mixturefurther comprises a surfactant and silica. The surfactants suitable foruse in the mixture provided herein include, but are not limited to,sodium lauryl sulfate, polyethylene stearates, polyethylene sorbitanfatty acid esters, polyoxyethylene castor oil derivatives,polyoxyethylene alkyl ethers, benzyl benzoate, cetrimide, cetyl alcohol,docusate sodium, glyceryl monooleate, glyceryl monostearate, glycerylpalmitostearate, lecithin, medium chain triglycerides, monoethanolamine,oleic acid, poloxamers, polyvinyl alcohol and sorbitan fatty acidesters. In a specific embodiment, the surfactant is sodium laurylsulfate.

In specific embodiments, the mixture of polyvinyl acetate and polyvinylpyrrolidone comprises 70-90% polyvinyl acetate and 15-20% polyvinylpyrrolidone. In a specific embodiment, the mixture consists of about 80%polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8% sodiumlauryl sulfate, and about 0.2% of silica. In one embodiment, the mixturecomprising polyvinyl acetate and polyvinyl pyrrolidone is KOLLIDON® SRpolyvinyl acetate/polyvinyl pyrrolidone (BASF); KOLLIDON® SR is a blendof 80% polyvinyl acetate and 19% povidone (also called polyvinylpyrrolidone) along with small quantities of sodium lauryl sulfate andsilica used as stabilizers (see Signet Chemical Corporation's websitepage for KOLLIDON® SR).

In some embodiments, the amount of the mixture comprising polyvinylacetate and polyvinyl pyrrolidone in the compressed core is in the rangeof about 10% w/w to about 40% w/w of the compressed core.

In some embodiments, the amount of the mixture comprising polyvinylacetate and polyvinyl pyrrolidone in the compressed core is in the rangeof about 10% w/w to about 35% w/w, about 10% w/w to about 30% w/w, about10% w/w to about 25% w/w, about 10% w/w to about 20% w/w, about 10% w/wto about 15% w/w, about 15% w/w to about 40% w/w, about 15% w/w to about35% w/w, about 15% w/w to about 30% w/w, about 15% w/w to about 25% w/w,about 15% w/w to about 20% w/w, about 20% w/w to about 40% w/w, about20% w/w to about 35% w/w, about 20% w/w to about 30% w/w, about 20% w/wto about 25% w/w, about 25% w/w to about 40% w/w, about 25% w/w to about35% w/w, about 25% w/w to about 30% w/w, about 30% w/w to about 40% w/w,about 30% w/w to about 35% w/w, or about 35% w/w to about 40% w/w of thecompressed core. In a specific embodiment, the amount of the mixturecomprising polyvinyl acetate and polyvinyl pyrrolidone in the compressedcore is in the range of about 20% w/w to about 30% w/w. In someembodiments, the amount of the mixture comprising polyvinyl acetate andpolyvinyl pyrrolidone in the compressed core is about 20% w/w, about20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w, about 22.5%w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about 24.5% w/w,about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5% w/w, about27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w, about 29% w/w,about 29.5% w/w, or about 30% w/w of the compressed core. In a specificembodiment, the amount of the mixture comprising polyvinyl acetate andpolyvinyl pyrrolidone in the compressed core is about 25% w/w of thecompressed core.

In addition to the polymers described herein, one or more fillers,binders, lubricants and the like may be used in the compressed core ofthe invention.

Suitable fillers include, as described in U.S. Pat. No. 8,858,993, butare not limited to, inorganic compounds such as the chloride, sulfate,and phosphate salts of potassium, sodium and magnesium as well ascalcium citrate, phosphate, lactate, gluconate and succinate salts. In aspecific embodiment, the filler is dibasic calcium phosphate dihydrate.

The concentration for the filler can be in the range of about 40% w/w toabout 60% w/w of the sustained release tablet. In a specific embodiment,the amount of the filler in the compressed core is in the range of about47% w/w to about 53% w/w of the sustained release tablet.

In some embodiments, the amount of the filler in the compressed core isin the range of about 40% w/w to about 65% w/w of the compressed core.In some embodiments, the amount of the filler in the compressed core isin the range of about 40% w/w to about 60% w/w about 40% w/w to about55% w/w, about 40% w/w to about 50% w/w, about 40% w/w to about 45% w/w,about 45% w/w to about 65% w/w, about 45% w/w to about 60% w/w, about45% w/w to about 55% w/w, about 45% w/w to about 50% w/w, about 50% w/wto about 65% w/w, about 50% w/w to about 60% w/w, about 50% w/w to about55% w/w, about 55% w/w to about 65% w/w, about 55% w/w to about 60% w/w,or about 60% w/w to about 65% w/w of the compressed core. In a specificembodiment, the amount of the filler in the compressed core is in therange of about 50% w/w to about 60% w/w of the compressed core. In someembodiments, the amount of the filler in the compressed core is about45% w/w, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w,about 50% w/w, about 51% w/w, about 52% w/w, about 53% w/w, about 54%w/w, about 55% w/w, about 56% w/w, about 57% w/w, about 58% w/w, about58% w/w, or about 60% w/w of the compressed core. In a specificembodiment, the amount of the filler in the compressed core is about 54%w/w of the compressed core. In another specific embodiment, the amountof the filler in the compressed core is about 55% w/w of the compressedcore. In a specific embodiment, the filler is dibasic calcium phosphatedihydrate in an amount of about 54% w/w of the compressed core. Inanother specific embodiment, the filler is dibasic calcium phosphatedihydrate in an amount of about 55% w/w of the compressed core.

Pharmaceutically acceptable binders suitable for use in the compressedcore of the present invention include, as described in U.S. Pat. No.8,858,993, but are not limited to, sucrose, gelatin, acacia, tragacanth,cellulose derivatives, povidone, and other binders known to thosefamiliar with pharmaceutical formulations.

The compressed core provided herein may further comprise one or morelubricants. Examples of lubricants include, but are not limited to,stearate salts; e.g., calcium stearate, magnesium stearate, zincstearate, and sodium stearyl fumarate; stearic acid; mineral oil;vegetable oil derivatives; talc; and the like. In a specific embodiment,the lubricant is magnesium stearate.

The concentration ranges for lubricants can be up to about 5% by weightof the sustained release tablet. In general, lubricants are present at aconcentration of 0.5-5% by weight of the sustained release tablet. In aspecific embodiment, the amount of lubricant in the compressed core isin the range of about 0.7% w/w to about 1.3% w/w of the sustainedrelease tablet. In some embodiments, the compressed core contains nolubricant.

In some embodiments, the amount of the lubricant in the compressed coreis up to about 5% w/w of the compressed core. In some embodiments, theamount of lubricant in the compressed core is in the range of about 0.5%w/w to about 5% w/w of the compressed core. In a specific embodiment,the amount of lubricant in the compressed core is in the range of about0.7% w/w to about 1.3% w/w of the compressed core. In a specificembodiment, the amount of the lubricant in the compressed core is about1% w/w of the compressed core. In a specific embodiment, the lubricantis magnesium stearate in an amount of about 1% w/w of the compressedcore.

In specific embodiments, the core comprising the 4-aminopyridine,polyethylene oxide polymer, mixture of polyvinyl acetate and polyvinylpyrrolidone, and optionally one or more fillers, binders and lubricantsis compressed to form intermediate tablets by methods well known in theart. The compressed core as described herein refers to such intermediatetablets. The compressed core (i.e., the intermediate tablets) is coatedwith a coating agent, and the resulting coated tablets are subjected toa curing step by exposing the coated tablets to a thermal treatment toyield the final sustained release tablets.

The release profile of 4-aminopyridine from the tablet can be modulatedby coating the compressed core (i.e., the intermediate tablet) with asuitable coating agent. In specific embodiments, the compressed core iscoated with a solution of ethyl cellulose or other cellulosic materials.In specific embodiments, the compressed core is coated with a colloidalsuspension or a dispersion of ethyl cellulose, optionally withadditional components such as light silicic acid anhydrides. Such lightsilicic anhydrides are described in The Pharmacopoeia of Japan XII andare commercially available under the trade name of, for example,AEROSIL-200 (produced by Nippon Aerosil Co., Ltd.). In some embodiments,an ethyl ether of cellulose having an ethoxy group content of 46 to 51%is employed as a coating agent. This type of ethyl cellulose iscommercially available under the trade name, for example, of ETHOCELSTANDARD (produced by Dow Chemical Co., Ltd.) and the like. In certainembodiments, the coating agent comprises a solution of ethyl cellulosein ethanol.

In a specific embodiment, the coating agent comprises pH independentethylcellulose. A “pH independent” ethylcellulose provides for a pHindependent release of the 4-aminopyridine from the tablet. In aspecific embodiment, the coating agent is an aqueous ethylcellulosedispersion. In a specific embodiment, the coating agent is SURELEASE®,commercially available from Colorcon. SURELEASE is a pH independentethylcellulose provided as an aqueous ethylcellulose dispersion. Anotheraqueous ethylcellulose dispersion that can be used as the coating agentis AQUACOAT® ECD Ethylcellulose Aqueous Dispersion, commerciallyavailable from FMC BioPolymer. As will be clear, the ethylcellulose coatcan contain other compounds in addition to ethylcellulose, butethylcellulose will be the predominant component by weight of theethylcellulose coat. In a specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is 8-10% w/w of thefinal sustained release tablet.

In one embodiment, the amount of the ethylcellulose coat surrounding thecompressed core is in the range of about 1% w/w to about 20% w/w of thecompressed core. In a specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is in the range ofabout 5% w/w to about 10% w/w of the compressed core. In someembodiments, the amount of the ethylcellulose coat surrounding thecompressed core is above 8% w/w and up to about 20% w/w of thecompressed core. In a specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is above 8% w/w andup to about 12% w/w or above 8% w/w and up to about 10% w/w of thecompressed core. In another specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is in the range ofabout 8% w/w to about 10% w/w of the compressed core. In someembodiments, the amount of the ethylcellulose coat surrounding thecompressed core is in the range of about 8% w/w to about 9.5% w/w, about8% w/w to about 9% w/w, 8% w/w to about 8.5% w/w, about 9% w/w to about10% w/w, about 9% w/w to about 9.5% w/w, or about 9.5% w/w to about 10%w/w of the compressed core. In some embodiments, the amount of theethylcellulose coat surrounding the compressed core is about 8% w/w,about 8.1% w/w, about 8.2% w/w, 8.3% w/w, about 8.4% w/w, about 8.5%w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w,about 9% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about 9.4%w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8% w/w,about 9.9% w/w, or about 10% w/w of the compressed core. In a specificembodiment, the amount of the ethylcellulose coat surrounding thecompressed core is about 8% w/w of the compressed core. In a specificembodiment, the amount of the ethylcellulose coat surrounding thecompressed core is about 9% w/w of the compressed core. In a specificembodiment, the amount of the ethylcellulose coat surrounding thecompressed core is about 10% w/w of the compressed core.

In some embodiments, the amount of the ethylcellulose coat surroundingthe compressed core is in the range of about 5% w/w to about 8% w/w ofthe compressed core. In some embodiments, the amount of theethylcellulose coat surrounding the compressed core is in the range ofabout 5% w/w to about 7% w/w of the compressed core. In someembodiments, the amount of the ethylcellulose coat surrounding thecompressed core is in the range of about 5% w/w to about 7.5% w/w, about5% w/w to about 7% w/w, about 5% w/w to about 6.5% w/w, about 5% w/w toabout 6% w/w, 5% w/w to about 5.5% w/w, about 5.5% w/w to about 8% w/w,about 5.5% w/w to about 7.5% w/w, about 5.5% w/w to about 7% w/w, about5.5% w/w to about 6.5% w/w, about 5.5% w/w to about 6% w/w, about 6% w/wto about 8% w/w, about 6% w/w to about 7.5% w/w, about 6% w/w to about7% w/w, about 6.5% w/w to about 8% w/w, about 6.5% w/w to about 7.5%w/w, about 6.5% w/w to about 7% w/w, about 7% w/w to about 8% w/w, about7% w/w to about 7.5% w/w, or about 7.5% w/w to about 8% w/w of thecompressed core. In some embodiments, the amount of the ethylcellulosecoat surrounding the compressed core is about 5% w/w, about 5.1% w/w,about 5.2% w/w, 5.3% w/w, about 5.4% w/w, about 5.5% w/w, about 5.6%w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w, about 6% w/w, about6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about 6.5%w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, about 6.9% w/w, orabout 7% w/w of the compressed core. In a specific embodiment, theamount of the ethylcellulose coat surrounding the compressed core isabout 5% w/w of the compressed core. In a specific embodiment, theamount of the ethylcellulose coat surrounding the compressed core isabout 6% w/w of the compressed core. In a specific embodiment, theamount of the ethylcellulose coat surrounding the compressed core isabout 7% w/w of the compressed core.

As will be clear, the amount of the ethylcellulose coat expressed interms of % w/w of the compressed core is equivalent to the amount of theethylcellulose coat expressed in terms of % weight gain. In other words,by way of example, if the weight of the compressed core is 100 mg, a 10%weight gain after coating the compressed core with the ethylcellulosecoat is an amount of the ethylcellulose coat that is equal to 10% w/w ofthe compressed core, which is 10 mg.

In one embodiment, the amount of the ethylcellulose coat surrounding thecompressed core is in the range of about 5% w/w to about 10% w/w of thecompressed core, and the amount of 4-aminopyridine in the compressedcore is in the range of about 4% w/w to about 6% w/w of the compressedcore. In a specific embodiment, the amount of the ethylcellulose coatsurrounding the compressed core is in the range of about 5% w/w to about10% w/w of the compressed core, and the amount of 4-aminopyridine in thecompressed core is about 22 mg. In another specific embodiment, theamount of the ethylcellulose coat surrounding the compressed core isabout 5% w/w of the compressed core, and the amount of 4-aminopyridinein the compressed core is in the range of about 4% w/w to about 6% w/wof the compressed core. In another specific embodiment, the amount ofthe ethylcellulose coat surrounding the compressed core is about 5% w/wof the compressed core, and the amount of 4-aminopyridine in thecompressed core is about 22 mg.

In a specific embodiment, the amount of the ethylcellulose coatsurrounding the compressed core is in the range of about 8% w/w to about10% w/w of the compressed core, and the amount of 4-aminopyridine in thecompressed core is in the range of about 4% w/w to about 6% w/w of thecompressed core. In another specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is in the range ofabout 8% w/w to about 10% w/w of the compressed core, and the amount of4-aminopyridine in the compressed core is about 22 mg. In anotherspecific embodiment, the amount of the ethylcellulose coat surroundingthe compressed core is about 9% w/w of the compressed core, and theamount of 4-aminopyridine in the compressed core is in the range ofabout 4% w/w to about 6% w/w of the compressed core. In another specificembodiment, the amount of the ethylcellulose coat surrounding thecompressed core is about 9% w/w of the compressed core, and the amountof 4-aminopyridine in the compressed core is about 22 mg.

In one embodiment, the amount of the ethylcellulose coat surrounding thecompressed core is in the range of about 5% w/w to about 7% w/w of thecompressed core, and the amount of 4-aminopyridine in the compressedcore is in the range of about 3% w/w to about 5% w/w of the compressedcore. In another specific embodiment, the amount of the ethylcellulosecoat surrounding the compressed core is about 6% w/w of the compressedcore, and the amount of 4-aminopyridine in the compressed core is in therange of about 3% w/w to about 5% w/w of the compressed core. In anotherspecific embodiment, the amount of the ethylcellulose coat surroundingthe compressed core is in the range of about 5% w/w to about 7% w/w ofthe compressed core, and the amount of 4-aminopyridine in the compressedcore is about 16.5 mg.

In one embodiment, the amount of the ethylcellulose coat surrounding thecompressed core is in the range of about 2% w/w to about 5% w/w of thecompressed core, and the amount of 4-aminopyridine in the compressedcore is about 16.5 mg. In another specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is about 3% w/w ofthe compressed core, and the amount of 4-aminopyridine in the compressedcore is about 16.5 mg. In another specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is about 4% w/w ofthe compressed core, and the amount of 4-aminopyridine in the compressedcore is about 16.5 mg. In another specific embodiment, the amount of theethylcellulose coat surrounding the compressed core is about 5% w/w ofthe compressed core, and the amount of 4-aminopyridine in the compressedcore is about 16.5 mg.

In one embodiment, the ratio of the amount of the ethylcellulose coatsurrounding the compressed core to the amount of 4-aminopyridine in thecompressed core is in the range of about 0.5:1 to about 3:1; wherein forcalculating said ratio, the amount of the ethylcellulose coat is theweight percentage of the ethylcellulose coat by weight of the compressedcore, and the amount of 4-aminopyridine is the weight percentage of4-aminopyridine by weight of the compressed core. In a preferredembodiment, this ratio of the amount of the ethylcellulose coat to4-aminopyridine is in the range of about 1:1 to about 2:1. In a specificembodiment, the ratio of the amount of the ethylcellulose coat to4-aminopyridine is about 1.6:1. In another specific embodiment, theratio of the amount of the ethylcellulose coat to 4-aminopyridine isabout 1.8:1.

In one embodiment, the ratio of the amount of the ethylcellulose coatsurrounding the compressed core to the amount of 4-aminopyridine in thecompressed core is in the range of about 0.1:1 to about 0.7:1; whereinfor calculating said ratio, the amount of the ethylcellulose coat is theweight percentage of the ethylcellulose coat by weight of the compressedcore, and the amount of 4-aminopyridine is the weight in milligrams of4-aminopyridine. In a preferred embodiment, this ratio of the amount ofthe ethylcellulose coat to 4-aminopyridine is in the range of about0.2:1 to about 0.5:1. In a specific embodiment, the ratio of the amountof the ethylcellulose coat to 4-aminopyridine is about 0.35:1. Inanother specific embodiment, the ratio of the amount of theethylcellulose coat to 4-aminopyridine is about 0.4:1.

In a specific embodiment, the coated compressed core is subjected to apost coating thermal treatment, also referred to as a curing step. In aspecific embodiment, the curing step comprises heating the coatedcompressed core to a temperature above 23° C. for a period of time of atleast 15 minutes. In a specific embodiment, the curing step comprisesexposing the coated compressed core to a temperature in the range of40-70° C. for a period of time of at least 15 minutes, 30 minutes, 1hour, 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42hours or 48 hours. In a specific embodiment, the period of time is atleast 1 hour. In a specific embodiment, the period of time is at least 6hours. In a specific embodiment, the period of time is at least 12hours. In a specific embodiment, the period of time is at least 18hours. In a specific embodiment, the period of time is at least 24hours. In a specific embodiment, the period of time is at least 30hours. In a specific embodiment, the period of time is at least 36hours. In a specific embodiment, the period of time is at least 42hours. In a specific embodiment, the period of time is at least 48hours. In a specific embodiment, the period of time is at least one ofthe foregoing, but not more than 48 hours. In a specific embodiment, thecoated compressed core is exposed to a temperature in the range of50-60° C. In a specific embodiment, the curing step comprises exposingthe coated compressed core to a temperature in the range of 40-70° C.for a period of time of at least 1 hour. In a specific embodiment, thecuring step comprises exposing the coated compressed core to atemperature in the range of 50-60° C. for a period of time of at least 1hour. In a specific embodiment, the curing step comprises exposing thecoated compressed core to a temperature in the range of 50-60° C. for aperiod of time in the range of 1-48 hours. The curing step of thepresent invention aims at stabilizing the drug release profile onstorage.

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine; (ii) a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000, wherein the amount of thepolyethylene oxide is in the range of about 12% w/w to about 20% w/w ofthe compressed core; (iii) a mixture consisting of about 80% polyvinylacetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium laurylsulfate, and about 0.2% of silica, wherein the amount of the mixture isin the range of about 20% w/w to about 30% w/w of the compressed core;(iv) dibasic calcium phosphate dihydrate, wherein the amount of dibasiccalcium phosphate dihydrate is in the range of about 50% w/w to about60% w/w of the compressed core; and (v) magnesium stearate, wherein theamount of magnesium stearate is in the range of about 0.7% w/w to about1.3% w/w of the compressed core; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore;

wherein the ratio of the amount of the ethylcellulose coat to the amountof 4-aminopyridine in the compressed core is in the range of about 1:1to about 2:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core, and the amount of 4-aminopyridine isthe weight percentage of 4-aminopyridine by weight of the compressedcore.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine; (ii) a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000, wherein the amount of thepolyethylene oxide is in the range of about 12% w/w to about 20% w/w ofthe compressed core; (iii) a mixture consisting of about 80% polyvinylacetate, about 19% polyvinyl pyrrolidone, about 0.8% sodium laurylsulfate, and about 0.2% of silica, wherein the amount of the mixture isin the range of about 20% w/w to about 30% w/w of the compressed core;(iv) dibasic calcium phosphate dihydrate, wherein the amount of dibasiccalcium phosphate dihydrate is in the range of about 50% w/w to about60% w/w of the compressed core; and (v) magnesium stearate, wherein theamount of magnesium stearate is in the range of about 0.7% w/w to about1.3% w/w of the compressed core; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore;

wherein the ratio of the amount of the ethylcellulose coat to the amountof 4-aminopyridine in the compressed core is in the range of about 0.2:1to about 0.5:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core, and the amount of 4-aminopyridine isthe weight in milligrams of 4-aminopyridine.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, said compressed core comprising 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 10% w/w of the compressed core.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises heating the coated compressed core to a temperature above 23°C. for a period of time of at least 15 minutes

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine; (ii) a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000; (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica; (iv) dibasic calciumphosphate dihydrate; and (v) magnesium stearate; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 10% w/w of the compressed core, and wherein the amountof 4-aminopyridine is in the range of about 4% w/w to about 6% w/w ofthe compressed core.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises exposing the coated compressed core to a temperature in therange of 50-60° C. for a period of time of at least 1 hour

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, wherein the amount of the polyethylene oxide is in the rangeof about 12% w/w to about 20% w/w of the compressed core; (iii) amixture consisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is in the range of about 20% w/w toabout 30% w/w of the compressed core; (iv) dibasic calcium phosphatedihydrate, wherein the amount of dibasic calcium phosphate dihydrate isin the range of about 50% w/w to about 60% w/w of the compressed core;and (v) magnesium stearate, wherein the amount of magnesium stearate isin the range of about 0.7% w/w to about 1.3% w/w of the compressed core;and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 10% w/w of the compressed core.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

In a specific embodiment, the sustained release tablet comprises:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core, (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore, (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core, (iv) dibasic calcium phosphate dihydrate in anamount of about 54% w/w of the compressed core, and (v) magnesiumstearate in an amount of about 1%; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 9% w/w of thecompressed core.

In a specific aspect of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 5% w/w of the compressedcore.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises exposing the coated compressed core to a temperature in therange of 50-60° C. for a period of time of at least 1 hour.

In another specific embodiment, the sustained release tablet comprises:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core, (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore, (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core, (iv) dibasic calcium phosphate dihydrate in anamount of about 54% w/w of the compressed core, and (v) magnesiumstearate in an amount of about 1%; and (b) an amount of anethylcellulose coat surrounding said compressed core, said amount of theethylcellulose coat being about 5% w/w of the compressed core.

In a specific aspect of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 5% w/w of the compressedcore.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises exposing the coated compressed core to a temperature in therange of 50-60° C. for a period of time of at least 1 hour.

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, said compressed core comprising 4-aminopyridine,a polyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, and a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 7% w/w of the compressed core.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises heating the coated compressed core to a temperature above 23°C. for a period of time of at least 15 minutes.

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine; (ii) a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000; (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica; (iv) dibasic calciumphosphate dihydrate; and (v) magnesium stearate; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 7% w/w of the compressed core, and wherein the amount of4-aminopyridine is in the range of about 3% w/w to about 5% w/w of thecompressed core.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises exposing the coated compressed core to a temperature in therange of 50-60° C. for a period of time of at least 1 hour

In one embodiment, provided herein is a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is about 3% w/wto about 5% w/w of the compressed core; (ii) a polyethylene oxide with amolecular weight between about 1,000,000 and 10,000,000, wherein theamount of the polyethylene oxide is in the range of about 12% w/w toabout 20% w/w of the compressed core; (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica, wherein the amount ofthe mixture is in the range of about 20% w/w to about 30% w/w of thecompressed core; (iv) dibasic calcium phosphate dihydrate, wherein theamount of dibasic calcium phosphate dihydrate is in the range of about50% w/w to about 60% w/w of the compressed core; and (v) magnesiumstearate, wherein the amount of magnesium stearate is in the range ofabout 0.7% w/w to about 1.3% w/w of the compressed core; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 7% w/w of the compressed core.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

In a specific embodiment, the sustained release tablet comprises:

(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 3% w/w to about 5% w/w of the compressed core, (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore, (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core, (iv) dibasic calcium phosphate dihydrate in anamount of about 55% w/w of the compressed core, and (v) magnesiumstearate in an amount of about 1%; and (b) an amount of anethylcellulose coat surrounding said compressed core, said amount of theethylcellulose coat being about 6% w/w of the compressed core.

In a specific aspect of the foregoing embodiments, the amount of4-aminopyridine in the compressed core is about 3.75% w/w of thecompressed core.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises exposing the coated compressed core to a temperature in therange of 50-60° C. for a period of time of at least 1 hour.

In one embodiment, the sustained release tablet provided herein isoptionally coated further with an aqueous film coat containing a smallquantity of 4-aminopyridine, referred to herein as the “4-AP drugovercoat” (or “immediate-release 4-AP drug overcoat”), which results inan initial burst (immediate release) of the 4-aminopyridine. Thisinitial burst is preferably followed by a zero order or near zero orderrelease of the drug from the remaining tablet over an extended period oftime. In one embodiment, the 4-AP drug overcoat comprises4-aminopyridine and one or more coating agents. In one embodiment, thecoating agent in the 4-AP drug overcoat compriseshydroxypropylmethylcellulose. In another embodiment, the coating agentin the 4-AP drug overcoat comprises polyvinylalcohol. In a specificembodiment, the coating agent in the 4-AP drug overcoat is from OPADRY®film coating system, commercially available from Colorcon. In a specificembodiment, the coating agent in the 4-AP drug overcoat comprisespolyvinyl alcohol, talc, polyethylene glycol, and polysorbate 80. In oneembodiment, the 4-AP drug overcoat further comprises a coloring agent.In one embodiment, the amount of 4-aminopyridine in the 4-AP drugovercoat is in the range of about 0.1% w/w to 1.5% w/w of the compressedcore. In another embodiment, the amount of 4-aminopyridine in the 4-APdrug overcoat is in the range of about 0.1% w/w to about 1.25% w/w,about 0.1% w/w to about 1% w/w, about 0.1% w/w to about 0.75% w/w, about0.1% w/w to about 0.50% w/w, about 0.1% w/w to about 0.25% w/w; about0.25% w/w to about 1.5% w/w, about 0.25% w/w to about 1.25% w/w, about0.25% w/w to about 1% w/w, about 0.25% w/w to about 0.75% w/w, about0.25% w/w to about 0.5% w/w, about 0.5% w/w to about 1.5% w/w, about0.5% w/w to about 1% w/w, about 0.5% w/w to about 0.75% w/w, about 1%w/w to about 1.5% w/w, or about 1% w/w to about 1.25% w/w of thecompressed core. In a specific embodiment, the amount of 4-aminopyridinein the 4-AP drug overcoat is about 0.1% w/w, about 0.15% w/w, about 0.2%w/w, about 0.25% w/w, about 0.3% w/w, about 0.35% w/w, about 0.4% w/w,about 0.45% w/w, about 0.5% w/w, about 0.55% w/w, about 0.6% w/w, about0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about 0.85%w/w, about 0.9% w/w, about 1% w/w, about 1.05% w/w, about 1.1% w/w,about 1.15% w/w, about 1.2% w/w, about 1.25% w/w, about 1.3% w/w, about1.35% w/w, about 1.4% w/w, about 1.45% w/w, or about 1.5% w/w of thecompressed core. In one embodiment, the amount of 4-aminopyridine in the4-AP drug overcoat is in the range of about 0.5 mg to about 6.5 mg. In aspecific embodiment, the amount of 4-aminopyridine in the 4-AP drugovercoat is in the range of about 0.5 mg to about 6 mg, about 0.5 mg toabout 5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 3 mg,about 0.5 mg to about 2 mg, about 0.5 mg to about 1 mg, about 1 mg toabout 6.5 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 6.5mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg toabout 3 mg, about 3 mg to about 6.5 mg, about 3 mg to about 5 mg, about3 mg to about 4 mg, about 4 mg to about 6.5 mg, or about 4 mg to about 5mg. In another specific embodiment, the amount of 4-aminopyridine in the4-AP drug overcoat is about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg,3.5 mg, 4 mg, 4.5 mg, or 5 mg. In one embodiment, the amount of thecoating agent in the 4-AP drug overcoat is in the range of about 3% w/wto about 15% w/w of the compressed core. In another embodiment, theamount of the coating agent in the 4-AP drug overcoat is in the range ofabout 3% w/w to about 12% w/w, about 3% w/w to about 10% w/w, about 3%w/w to about 7.5% w/w, about 3% w/w to about 5% w/w, about 5% w/w toabout 12% w/w, about 5% w/w to about 10% w/w, about 5% w/w to about 7.5%w/w, about 7.5% w/w to about 12% w/w, about 7.5% w/w to about 10% w/w,or about 10% w/w to about 12% w/w of the compressed core. In a specificembodiment, the amount of the coating agent in the 4-AP drug overcoat is7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8%, 8.1%, 8.2%,8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9%, 9.1%, 9.2%, 9.3%, 9.4%,9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%,10.6%, 10.7%, 10.8%, 10.9%, or 11%, w/w of the compressed core. In oneembodiment, the sustained release tablet provided herein is not coatedwith a 4-AP drug overcoat. In one embodiment, the sustained releasetablet provided herein is not coated with an immediate release drugovercoat (of any drug).

In specific embodiments, the sustained release tablets described hereinprovide for the release of 4-aminopyridine at a sustained rate such thata therapeutically beneficial blood level of the 4-aminopyridine ismaintained over a period of at least about 12 hours, preferably about 24hours or more. In specific embodiments, the sustained release tabletsdescribed herein provide for the release of 4-aminopyridine at asustained rate such that a therapeutically beneficial blood level of the4-aminopyridine is maintained over a period of at least about 18 hours.Preferably, the amount of the 4-aminopyridine in the sustained releasetablets of the present invention establishes a therapeutically usefulplasma concentration through once daily administration of the sustainedrelease tablet. In one embodiment, the sustained release tabletdescribed herein releases an amount of 4-aminopyridine that istherapeutically effective over a period of 24 hours upon administrationto a human patient or in physiological medium. In one embodiment, thesustained release tablet described herein releases an amount of4-aminopyridine that is therapeutically effective over a period of 12 or18 hours upon administration to a human patient or in physiologicalmedium In one embodiment, the sustained release tablet is suitable foronce daily oral administration; i.e., the sustained release tabletprovides a therapeutically effective amount of 4-aminopyridine to ahuman patient upon once daily oral administration.

The sustained release tablets described herein provide sustained releaseof the active substance 4-aminopyridine when subjected to an in vitrodissolution test. The in vitro dissolution test can be carried outaccording to standard procedures published by USP NF, <711> Dissolution.

In one embodiment, the dissolution profile of the sustained releasetablets described herein is determined by subjecting the sustainedrelease tablets to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium. In another embodiment, thedissolution profile of the sustained release tablets described herein isdetermined by subjecting the sustained release tablets to an in vitrodissolution test employing 50 mM Phosphate Buffer, pH 6.8 as dissolutionmedium.

In some embodiments, provided herein are sustained release tabletscomprising 4-aminopyridine, wherein the release of the 4-aminopyridine,upon subjecting the sustained release tablet to an in vitro dissolutiontest employing 50 mM Phosphate Buffer, pH 6.8 as dissolution medium andthe conditions described in Table 2, is as follows: (a) within the first2 hours after the start of the test at most 30% w/w of the total amountof the 4-aminopyridine contained in the sustained release tablet isreleased. In a preferred embodiment, the sustained release tablet thatis subjected to the dissolution test is a tablet in which4-aminopyridine is present only in the compressed core (which tablet canbe the final oral dosage form of a tablet that does not have animmediate release drug overcoat, or can be the tablet that has not yetbeen coated with the drug overcoat in an embodiment where the final oraldosage form will have a drug overcoat).

In some embodiments, the release of the 4-aminopyridine, upon subjectingthe sustained release tablet to an in vitro dissolution test employing50 mM Phosphate Buffer, pH 6.8 as dissolution medium and the conditionsdescribed in Table 2, is as follows: (a) within the first 2 hours afterthe start of the test at most 30% w/w of the total amount of the4-aminopyridine contained in the sustained release tablet is released;and (b) within the first 24 hours after the start of the test at least80% w/w of the total amount of the 4-aminopyridine contained in thesustained release tablet is released. In a preferred embodiment, thesustained release tablet that is subjected to the dissolution test is atablet in which 4-aminopyridine is present only in the compressed core(which tablet can be the final oral dosage form of a tablet that doesnot have an immediate release drug overcoat, or can be the tablet thathas not yet been coated with the drug overcoat in an embodiment wherethe final oral dosage form will have a drug overcoat).

In a specific embodiment, provided herein are sustained release tabletscomprising 4-aminopyridine, wherein the release of the 4-aminopyridine,upon subjecting the sustained release tablet to an in vitro dissolutiontest employing 50 mM Phosphate Buffer, pH 6.8 as dissolution medium andthe conditions described in Table 2, is as follows: (a) within the first2 hours after the start of the test at most 20% w/w of the total amountof the 4-aminopyridine contained in the sustained release tablet isreleased. In some embodiments, the release of the 4-aminopyridine, uponsubjecting the sustained release tablet to an in vitro dissolution testemploying 50 mM Phosphate Buffer, pH 6.8 as dissolution medium and theconditions described in Table 2, is as follows: (a) within the first 2hours after the start of the test at most 20% w/w of the total amount ofthe 4-aminopyridine contained in the sustained release tablet isreleased; and (b) within the first 24 hours after the start of the testat least 80% w/w of the total amount of the 4-aminopyridine contained inthe sustained release tablet is released. In a preferred embodiment, thesustained release tablet that is subjected to the dissolution test is atablet in which 4-aminopyridine is present only in the compressed core(which tablet can be the final oral dosage form of a tablet that doesnot have an immediate release drug overcoat, or can be the tablet thathas not yet been coated with the drug overcoat in an embodiment wherethe final oral dosage form will have a drug overcoat).

In a specific embodiment, the release of the 4-aminopyridine, uponsubjecting the sustained release tablet to an in vitro dissolution testemploying 50 mM Phosphate Buffer, pH 6.8 as dissolution medium and theconditions described in Table 2, is as follows: (a) within the first 2hours after the start of the test at most 30% w/w of the total amount ofthe 4-aminopyridine contained in the sustained release tablet isreleased; (b) within the first 10 hours after the start of the test atleast 50% w/w of the total amount of the 4-aminopyridine contained inthe sustained release tablet is released; and (c) within the first 18hours after the start of the test at least 75% w/w of the total amountof the 4-aminopyridine contained in the sustained release tablet isreleased. In a preferred embodiment, the sustained release tablet thatis subjected to the dissolution test is a tablet in which4-aminopyridine is present only in the compressed core (which tablet canbe the final oral dosage form of a tablet that does not have animmediate release drug overcoat, or can be the tablet that has not yetbeen coated with the drug overcoat in an embodiment where the final oraldosage form will have a drug overcoat).

In a specific embodiment, the release of the 4-aminopyridine, uponsubjecting the sustained release tablet to an in vitro dissolution testemploying 50 mM Phosphate Buffer, pH 6.8 as dissolution medium and theconditions described in Table 2, is as follows: (a) within the first 2hours after the start of the test at most 30% w/w of the total amount ofthe 4-aminopyridine contained in the sustained release tablet isreleased; (b) within the first 10 hours after the start of the test atleast 40% w/w of the total amount of the 4-aminopyridine contained inthe sustained release tablet is released; and (c) within the first 24hours after the start of the test at least 80% w/w of the total amountof the 4-aminopyridine contained in the sustained release tablet isreleased. In a preferred embodiment, the sustained release tablet thatis subjected to the dissolution test is a tablet in which4-aminopyridine is present only in the compressed core (which tablet canbe the final oral dosage form of a tablet that does not have animmediate release drug overcoat, or can be the tablet that has not yetbeen coated with the drug overcoat in an embodiment where the final oraldosage form will have a drug overcoat).

In a specific embodiment, the release of the 4-aminopyridine, uponsubjecting the sustained release tablet to an in vitro dissolution testemploying 50 mM Phosphate Buffer, pH 6.8 as dissolution medium and theconditions described in Table 2, is as follows: (a) within the first 2hours after the start of the test at most 30% w/w of the total amount ofthe 4-aminopyridine contained in the sustained release tablet isreleased; (b) within the first 10 hours after the start of the test atleast 40% w/w and at most 85% w/w of the total amount of the4-aminopyridine contained in the sustained release tablet is released;and (c) within the first 24 hours after the start of the test at least80% w/w of the total amount of the 4-aminopyridine contained in thesustained release tablet is released. In a preferred embodiment, thesustained release tablet that is subjected to the dissolution test is atablet in which 4-aminopyridine is present only in the compressed core(which tablet can be the final oral dosage form of a tablet that doesnot have an immediate release drug overcoat, or can be the tablet thathas not yet been coated with the drug overcoat in an embodiment wherethe final oral dosage form will have a drug overcoat).

In a specific embodiment, the release of the 4-aminopyridine, uponsubjecting the sustained release tablet to an in vitro dissolution testemploying 50 mM Phosphate Buffer, pH 6.8 as dissolution medium and theconditions described in Table 2, is as follows: (a) within the first 2hours after the start of the test at most 30% w/w of the total amount ofthe 4-aminopyridine contained in the sustained release tablet isreleased; (b) within the first 6 hours after the start of the test atleast 10% w/w and at most 65% of the total amount of the 4-aminopyridinecontained in the sustained release tablet is released; (c) within thefirst 10 hours after the start of the test at least 40% w/w and at most85% w/w of the total amount of the 4-aminopyridine contained in thesustained release tablet is released; and (d) within the first 24 hoursafter the start of the test at least 80% w/w of the total amount of the4-aminopyridine contained in the sustained release tablet is released.In a preferred embodiment, the sustained release tablet that issubjected to the dissolution test is a tablet in which 4-aminopyridineis present only in the compressed core (which tablet can be the finaloral dosage form of a tablet that does not have an immediate releasedrug overcoat, or can be the tablet that has not yet been coated withthe drug overcoat in an embodiment where the final oral dosage form willhave a drug overcoat).

In a specific embodiment, the release of the 4-aminopyridine, uponsubjecting the sustained release tablet to an in vitro dissolution testemploying 50 mM Phosphate Buffer, pH 6.8 as dissolution medium and theconditions described in Table 2, is as follows: (a) within the first 2hours after the start of the test at most 30% w/w of the total amount ofthe 4-aminopyridine contained in the sustained release tablet isreleased; (b) within the first 6 hours after the start of the test atmost 60% w/w and at least 10% w/w of the total amount of the4-aminopyridine contained in the sustained release tablet is released;(c) within the first 10 hours after the start of the test at most 80%w/w and at least 30% w/w of the total amount of the 4-aminopyridinecontained in the sustained release tablet is released; and (d) withinthe first 24 hours after the start of the test at least 85% w/w of thetotal amount of the 4-aminopyridine contained in the sustained releasetablet is released. In a preferred embodiment, the sustained releasetablet that is subjected to the dissolution test is a tablet in which4-aminopyridine is present only in the compressed core (which tablet canbe the final oral dosage form of a tablet that does not have animmediate release drug overcoat, or can be the tablet that has not yetbeen coated with the drug overcoat in an embodiment where the final oraldosage form will have a drug overcoat).

In one embodiment, the sustained release tablet described hereindisplays a release profile, when tested under the conditions describedin Table 2, that when depicted as in FIG. 1, 3, or 4 to graph % releaseversus time in hours is plus or minus 20% of the data plot depicted inFIG. 1, 3 or 4. In a preferred embodiment, the sustained release tabletthat is subjected to the dissolution test is a tablet in which4-aminopyridine is present only in the compressed core (which tablet canbe the final oral dosage form of a tablet that does not have animmediate release drug overcoat, or can be the tablet that has not yetbeen coated with the drug overcoat in an embodiment where the final oraldosage form will have a drug overcoat).

The in vivo release mechanism of a drug from a sustained release tabletmay be altered if the sustained release formulation is administered withalcohol, leading to dose dumping. See, Anand et al., 2011, AAPS J.,13(3):328-335. In a specific embodiment, the total amount of the4-aminopyridine released, upon subjecting the sustained release tabletto an in vitro dissolution test employing 0.1 N hydrochloric acidcontaining 40% alcohol (ethanol) as a dissolution medium, within thefirst 2 hours of the in vitro dissolution test is not greater than thetotal amount of 4-aminopyridine released within the first 2 hours of anin vitro dissolution test employing 0.1 N hydrochloric acid asdissolution medium.

In a specific embodiment, a sustained release tablet provided hereinexhibits substantially no dose dumping in the presence of food (i.e.,there are not clinically relevant differences in one or morepharmacokinetic parameters) between fed and fasted states uponadministration to patients.

Methods of Making

Provided herein are methods of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (v) magnesiumstearate;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core; and(c) curing the coated compressed core by exposing it to a temperature inthe range of 40-70° C. for a period of time of at least 15 minutes,wherein the ratio of the amount of the ethylcellulose coat to the amountof 4-aminopyridine in the compressed core is in the range of about 0.5:1to about 3:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core, and the amount of 4-aminopyridine isthe weight percentage of 4-aminopyridine by weight of the compressedcore.

In a preferred embodiment of the foregoing embodiment, the ratio of theamount of the ethylcellulose coat to 4-aminopyridine is in the range ofabout 1:1 to about 2:1.

Also, provided herein are methods of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (v) magnesiumstearate;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core; and(c) curing the coated compressed core by exposing it to a temperature inthe range of 40-70° C. for a period of time of at least 15 minutes,wherein the ratio of the amount of the ethylcellulose coat to the amountof 4-aminopyridine in the compressed core is in the range of about 0.1:1to about 0.7:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core, and the amount of 4-aminopyridine isthe weight in milligrams of 4-aminopyridine.

In a preferred embodiment of the foregoing embodiment, the ratio of theamount of the ethylcellulose coat to 4-aminopyridine is in the range ofabout 0.2:1 to about 0.5:1.

Also, provided herein are methods of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (v) magnesiumstearate;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingin the range of about 8% w/w to about 10% w/w of the sustained releasetablet; and(c) curing the coated compressed core by heating the coated compressedcore to a temperature above 23° C. for a period of time of at least 15minutes.

Also, provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (v) magnesiumstearate;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingin the range of about 5% w/w to about 10% w/w of the compressed core;and(c) curing the coated compressed core by exposing it to a temperature inthe range of 40-70° C. for a period of time of at least 15 minutes.

In a specific embodiment of the foregoing method of making, the amountof the ethylcellulose coat is about 9% w/w of the compressed core andthe amount of 4-aminopyridine is in the range of about 4% w/w to about6% w/w of the compressed core. In another specific embodiment of theforegoing method of making, the amount of the ethylcellulose coat isabout 5% w/w of the compressed core and the amount of 4-aminopyridine isin the range of about 4% w/w to about 6% w/w of the compressed core.

Also, provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, (ii) apolyethylene oxide with a molecular weight between about 1,000,000 and10,000,000, (iii) a mixture comprising polyvinyl acetate and polyvinylpyrrolidone; (iv) dibasic calcium phosphate dihydrate, and (v) magnesiumstearate;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingin the range of about 5% w/w to about 7% w/w of the compressed core; and(c) curing the coated compressed core by exposing it to a temperature inthe range of 40-70° C. for a period of time of at least 15 minutes.

In a specific embodiment of the foregoing methods of making, the amountof the ethylcellulose coat is about 6% w/w of the compressed core andthe amount of 4-aminopyridine is in the range of about 3% w/w to about5% w/w of the compressed core.

In a specific embodiment, the curing step comprises exposing the coatedcompressed core to a temperature in the range of 40-70° C. for a periodof time of at least 15 minutes, 30 minutes or 1 hour. In a specificembodiment, the curing step comprises exposing the coated compressedcore to a temperature in the range of 40-70° C. for a period of time ofat least 1 hour.

Also provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, whereinthe amount of 4-aminopyridine is in the range of about 4% w/w to about6% w/w of the compressed core, (ii) a polyethylene oxide with amolecular weight of 7,000,000, wherein the amount of the polyethyleneoxide is about 15% w/w of the compressed core, (iii) a mixtureconsisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is about 25% w/w of the compressedcore; (iv) dibasic calcium phosphate dihydrate, wherein the amount ofdibasic calcium phosphate dihydrate is about 54% w/w of the compressedcore; and (v) magnesium stearate, wherein the amount of magnesiumstearate is about 1% w/w of the compressed core;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingabout 9% w/w of the compressed core; and(c) curing the coated compressed core by exposing it to a temperature inthe range of 50-60° C. for a period of time of at least 1 hour.

In a specific embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 22 mg.

Also provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, whereinthe amount of 4-aminopyridine is in the range of about 4% w/w to about6% w/w of the compressed core, (ii) a polyethylene oxide with amolecular weight of 7,000,000, wherein the amount of the polyethyleneoxide is about 15% w/w of the compressed core, (iii) a mixtureconsisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is about 25% w/w of the compressedcore; (iv) dibasic calcium phosphate dihydrate, wherein the amount ofdibasic calcium phosphate dihydrate is about 54% w/w of the compressedcore; and (v) magnesium stearate, wherein the amount of magnesiumstearate is about 1% w/w of the compressed core;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingabout 5% w/w of the compressed core; and(c) curing the coated compressed core by exposing it to a temperature inthe range of 50-60° C. for a period of time of at least 1 hour.

In a specific embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 22 mg.

Also provided herein is a method of making a sustained release tabletcomprising 4-aminopyridine, which method comprises:

(a) forming a compressed core comprising (i) 4-aminopyridine, whereinthe amount of 4-aminopyridine is in the range of about 3% w/w to about5% w/w of the compressed core, (ii) a polyethylene oxide with amolecular weight of 7,000,000, wherein the amount of the polyethyleneoxide is about 15% w/w of the compressed core, (iii) a mixtureconsisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is about 25% w/w of the compressedcore; (iv) dibasic calcium phosphate dihydrate, wherein the amount ofdibasic calcium phosphate dihydrate is about 55% w/w of the compressedcore; and (v) magnesium stearate, wherein the amount of magnesiumstearate is about 1% w/w of the compressed core;(b) coating the compressed core with an amount of ethylcellulose to forma coated compressed core, said amount of the ethylcellulose coat beingabout 6% w/w of the compressed core; and(c) curing the coated compressed core by exposing it to a temperature inthe range of 50-60° C. for a period of time of at least 1 hour.

In a specific embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 16.5 mg.

In specific embodiments, the methods of making a sustained releasetablet comprise, or consist essentially, or consist of, the steps asdescribed herein.

The core is typically formed by first blending the active drug substance(4-aminopyridine), the polymeric components of the formulation, andadditional excipients (e.g., filler or binder) for a brief period oftime (e.g., 5-20 minutes). This is followed by addition of a suitablelubricant and further blending the mixture to a uniform new blend. Theresulting blend is then compressed to intermediate tablets by methodsknown in the art.

In a specific embodiment, the method of forming the compressed corecomprises:

(a) blending the 4-aminopyridine, polyethylene oxide, the mixturecomprising polyvinyl acetate and polyvinyl pyrrolidone, and dibasiccalcium phosphate dihydrate to form a blended mixture;(b) adding magnesium stearate to the blended mixture to form a newblend; and(c) compressing the new blend to form a compressed core. In a specificembodiment, the blended mixture and new blend are formed by dryblending.

In a specific embodiment, the polyethylene oxide has a molecular weightbetween 4,000,000 and 8,000,000. In another specific embodiment, thepolyethylene oxide has a molecular weight of 7,000,000. In anotherspecific embodiment, the polyethylene oxide is POLYOX WSR-303,commercially available from Dow Chemical Co. In a specific embodiment,the amount of the polyethylene oxide in the compressed core is in therange of about 10% w/w to about 20% w/w of the compressed core.

In a specific embodiment, the mixture comprising polyvinyl acetate andpolyvinyl pyrrolidone consists of about 80% polyvinyl acetate, about 19%polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2%of silica. In one embodiment, the mixture comprising polyvinyl acetateand polyvinyl pyrrolidone is KOLLIDON® SR polyvinyl acetate/polyvinylpyrrolidone (BASF); KOLLIDON® SR is a blend of 80% polyvinyl acetate and19% povidone (also called polyvinyl pyrrolidone) along with smallquantities of sodium lauryl sulfate and silica used as stabilizers (seeSignet Chemical Corporation's website page for KOLLIDON® SR). In aspecific embodiment, the amount of the mixture comprising polyvinylacetate and polyvinyl pyrrolidone in the compressed core is in the rangeof about 20% w/w to about 30% w/w of the compressed core.

In a specific embodiment, the amount of dibasic calcium phosphatedihydrate in the compressed core is in the range of about 47% w/w toabout 53% w/w of the sustained release tablet. In another specificembodiment, the amount of dibasic calcium phosphate dihydrate in thecompressed core is in the range of about 50% w/w to about 60% w/w of thecompressed core.

In a specific embodiment, the amount of magnesium stearate in thecompressed core is in the range of about 0.7% w/w to about 1.3% w/w ofthe sustained release tablet. In another specific embodiment, the amountof magnesium stearate in the compressed core is in the range of about0.7% w/w to about 1.3% w/w of the compressed core.

The coating of the compressed core (i.e., intermediate tablets) isperformed by using methods well known in the art, as described in U.S.Pat. No. 8,858,993. In a specific embodiment, the coating processdescribed herein includes film coating. Tablet coating equipment mayinclude spray guns, coating pans, polishing pans, solution tanks,blenders and mixers, homogenizers, mills, peristaltic pumps, fans, steamjackets, exhaust and heating pipes, scales and filters. In a specificembodiment, the coating method involves spray coating.

As described in U.S. Pat. No. 8,858,993, tablet coating typically takesplace in a controlled atmosphere inside a perforated rotating drum.Angled baffles fitted into the drum and air flow inside the drum canprovide means of mixing the tablet bed. As a result, the tablets arelifted and turned from the sides into the center of the drum, exposingeach tablet surface to an even amount of deposited/sprayed coating. Theliquid spray coating is then dried onto the tablets by heated air drawnthrough the tablet bed from an inlet fan. The air flow is typicallyregulated for temperature and volume to provide controlled drying andextracting rates, and at the same time, maintaining the drum pressureslightly negative relative to the room in order to provide a completelyisolated process atmosphere for the operator.

In a specific embodiment, the coated compressed core is subjected to apost coating thermal treatment, also referred to as a curing step. In aspecific embodiment, the curing step comprises heating the coatedcompressed core to a temperature above 23° C. for a period of time of atleast 15 minutes. In a specific embodiment, the curing step comprisesexposing the coated compressed core to a temperature in the range of40-70° C. for a period of time of at least 15 minutes, 30 minutes, 1hour, 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42hours or 48 hours. In a specific embodiment, the period of time is atleast 1 hour. In a specific embodiment, the period of time is at least 6hours. In a specific embodiment, the period of time is at least 12hours. In a specific embodiment, the period of time is at least 18hours. In a specific embodiment, the period of time is at least 24hours. In a specific embodiment, the period of time is at least 30hours. In a specific embodiment, the period of time is at least 36hours. In a specific embodiment, the period of time is at least 42hours. In a specific embodiment, the period of time is at least 48hours. In a specific embodiment, the coated compressed core is exposedto a temperature in the range of 50-60° C. In a specific embodiment, thecuring step comprises exposing the coated compressed core to atemperature in the range of 40-70° C. for a period of time of at least 1hour. In a specific embodiment, the curing step comprises exposing thecoated compressed core to a temperature in the range of 50-60° C. for aperiod of time of at least 1 hour. In a specific embodiment, the curingstep comprises exposing the coated compressed core to a temperature inthe range of 50-60° C. for a period of time in the range of 1-48 hours.The curing step of the present invention aims at stabilizing the drugrelease profile on storage.

In one embodiment, after the curing step the sustained release tablet isoptionally coated further with an aqueous film coat containing a smallquantity of 4-aminopyridine, referred to herein as the “4-AP drugovercoat” (or “immediate release 4-AP drug overcoat”), which results inan initial burst (immediate release) of the 4-aminopyridine. Thisinitial burst is preferably followed by a zero order or near zero orderrelease of the drug from the remaining tablet over an extended period oftime. In one embodiment, the 4-AP drug overcoat comprises4-aminopyridine and one or more coating agents. In one embodiment, thecoating agent in the 4-AP drug overcoat compriseshydroxypropylmethylcellulose. In another embodiment, the coating agentin the 4-AP drug overcoat comprises polyvinylalcohol. In a specificembodiment, the coating agent in the 4-AP drug overcoat is from OPADRY®film coating system, commercially available from Colorcon. In a specificembodiment, the coating agent in the 4-AP drug overcoat comprisespolyvinyl alcohol, talc, polyethylene glycol, and polysorbate 80. In oneembodiment, the 4-AP drug overcoat further comprises a coloring agent. Asolution of the 4-AP drug overcoat is typically prepared by dissolving acoating agent in a suitable solvent (e.g., water), followed by adding4-aminopyridine and stirring to obtain a clear solution. The solution ofthe 4-AP drug overcoat can be applied to the dried coated compressedcores by methods well known in the art to achieve the desired coatweight gain. In one embodiment, the solution is applied by spraycoating. After the 4-AP drug overcoat is applied, the resulting tabletscan be dried, e.g., for up to 1 h at a temperature of about 50-60° C.

In a specific embodiment the sustained release tablet of the presentinvention, aside from any immediate release of 4-aminopyridine due tothe presence of a 4-AP drug overcoat, provides a zero-order ornear-zero-order release of the 4-aminopyridine. In a preferredembodiment, the release is zero-order.

In specific embodiments, the sustained release tablets discussed hereinprovide for the release of 4-aminopyridine at a sustained rate such thata therapeutically beneficial blood level of the 4-aminopyridine ismaintained over a period of at least about 12 hours, preferably about 24hours or more. In another specific embodiment, the sustained releasetablets discussed herein provide for the release of 4-aminopyridine at asustained rate such that a therapeutically beneficial blood level of the4-aminopyridine is maintained over a period of at least about 18 hours.Preferably, the amount of the 4-aminopyridine in the sustained releasetablets of the present invention establish a therapeutically usefulplasma concentration through once daily administration of the sustainedrelease tablet. In one embodiment, the sustained release tabletdescribed herein comprises an amount of 4-aminopyridine that istherapeutically effective over a period of 24 hours. In one embodiment,the sustained release tablet is suitable for once daily oraladministration; i.e., the sustained release tablet provides atherapeutically effective of 4-aminopyridine to a human patient upononce daily oral administration.

As used herein, and unless otherwise indicated, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, or 3 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%,0.25%, 0.2%, 0.1% or 0.05% of a given value or range.

5.2 Methods of Treatment

Provided herein are methods of treating a neurological disorder in apatient in need thereof comprising orally administering to the patient asustained release 4-aminopyridine tablet as disclosed herein.

In one embodiment, provided herein are methods of treating aneurological disorder in a patient in need thereof comprising orallyadministering to the patient once daily a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 54% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core;

and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 9% w/w of thecompressed core.

In one embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 17.5 mg, about 18 mg,about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg,about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg,about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg,about 26 mg, or about 26.5 mg. In a specific embodiment of the foregoingembodiment, the amount of 4-aminopyridine in the compressed core isabout 22 mg.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

In one embodiment, provided herein are methods of treating aneurological disorder in a patient in need thereof comprising orallyadministering to the patient once daily a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 4% w/w to about 6% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 54% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core; and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 5% w/w of thecompressed core.

In one embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 17.5 mg, about 18 mg,about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg,about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg,about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg,about 26 mg, or about 26.5 mg. In a specific embodiment of the foregoingembodiment, the amount of 4-aminopyridine in the compressed core isabout 22 mg.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

In one embodiment, provided herein are methods of treating aneurological disorder in a patient in need thereof comprising orallyadministering to the patient once daily a sustained release tabletcomprising:

(a) a compressed core, wherein said compressed core comprises (i)4-aminopyridine, wherein the amount of 4-aminopyridine is in the rangeof about 3% w/w to about 5% w/w of the compressed core; (ii) apolyethylene oxide with a molecular weight of 7,000,000, wherein theamount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 55% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core;

and

(b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being about 6% w/w of thecompressed core.

In one embodiment of the foregoing embodiment, the amount of4-aminopyridine in the compressed core is about 13 mg, about 13.5 mg,about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg,about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg,about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg,about 21.5 mg or about 22 mg. In a specific embodiment of the foregoingembodiment, the amount of 4-aminopyridine in the compressed core isabout 16.5 mg.

In a specific embodiment of the foregoing, the sustained release tabletis the product of a process comprising a curing step after coating thecompressed core with ethylcellulose, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of50-60° C. for a period of time of at least 1 hour.

“Patient” is defined herein to include animals, such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens,turkeys, quails, or guinea pigs and the like. In one embodiment, thepatient is a mammal. In a preferred embodiment, the patient is a humanpatient.

In a specific embodiment, the human patient is an adult (e.g., greaterthan 16 years of age). In another specific embodiment, the patient is apediatric patient (e.g., age 2-16). In one embodiment, the age of thepediatric patient is at least 6 years. In another specific embodiment,the human patient is an adolescent (e.g., age 12-16). In anotherspecific embodiment, the patient is a child (e.g. age 2-12). In oneembodiment, the age of the child is at least 6 years.

In one embodiment, the administering to the patient is performed oncedaily. In another embodiment, the administering to the patient isperformed twice daily.

The neurological disorder is a neurological disorder amenable totreatment by 4-aminopyridine. In certain embodiments, the neurologicaldisorder is a neurological disease including, but not limited to,multiple sclerosis and stroke. In a specific embodiment, theneurological disorder is multiple sclerosis. In another specificembodiment, the neurological disorder is stroke. In some embodiments,the neurological disorder is an impairment associated with aneurological disease. In one embodiment, the neurological disorder is awalking impairment associated with multiple sclerosis. In a specificembodiment, the method of treatment is to improve walking or to increasewalking speed in a multiple sclerosis patient. In a specific embodiment,the method of treatment is to improve walking or to increase walkingspeed in a stroke patient. In one embodiment, the neurological disorderis a neurocognitive or a neuropsychiatric impairment associated withmultiple sclerosis. In one embodiment, the neurological disorder is asensorimotor impairment associated with stroke. In one embodiment, theneurological disorder is a walking impairment associated with stroke.

In a specific embodiment, the invention provides a method of improvingwalking comprising administering once daily to a patient (e.g., amultiple sclerosis patient) a sustained release tablet provided herein.

In one embodiment, the sustained release 4-aminopyridine tablet asdisclosed herein is orally administered to a patient with renalimpairment, for example, a patient who is mildly or moderately renallyimpaired. In one embodiment, the renal impairment is mild renalimpairment. In one embodiment, the renal impairment is moderate renalimpairment. In one embodiment, the renal impairment is severe renalimpairment. In one embodiment, the renal impairment is moderate orsevere renal impairment. In another embodiment, the sustained release4-aminopyridine tablet is orally administered to a patient who is notseverely renal impaired. In one embodiment, the patient is classified ashaving mild renal impairment when the patient has a creatinine clearancevalue in the range of 51-80 mL/min. In another embodiment, the patientis classified as having mild renal impairment when the patient has acreatinine clearance value in the range of 60-89 mL/min. In yet anotherembodiment, the patient is classified as having mild renal impairmentwhen the patient has an estimated glomerular filtration rate in therange of 60-89 mL/min/1.73 m². In one embodiment, the patient isclassified as having moderate renal impairment when the patient has acreatinine clearance value in the range of 30-59 mL/min. In yet anotherembodiment, the patient is classified as having moderate renalimpairment when the patient has an estimated glomerular filtration ratein the range of 30-59 mL/min/1.73 m². In one embodiment, the patient isclassified as having severe renal impairment when the patient has acreatinine clearance value in the range of 15-29 mL/min. In yet anotherembodiment, the patient is classified as having severe renal impairmentwhen the patient has an estimated glomerular filtration rate in therange of 15-29 mL/min/1.73 m².

In a specific embodiment, the sustained release tablet as disclosedherein is orally administered once daily to an adult or adolescentpatient, wherein the compressed core of the sustained release tabletcomprises 4-aminopyridine in an amount in the range of about 5 mg toabout 40 mg. In a specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is in the range of about 5 mg toabout 35 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, about5 mg to about 20 mg, about 5 mg to about 15 mg, about 5 mg to about 10mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mgto about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg,about 10 mg to about 15 mg, about 15 mg to about 40 mg, about 15 mg toabout 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg,about 15 mg to about 20 mg, about 20 mg to about 40 mg, about 20 mg toabout 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg,about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg toabout 30 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, orabout 35 mg to about 40 mg. In another specific embodiment of theforegoing, the amount of 4-aminopyridine in the compressed core is about16 mg, about 16.2 mg, about 16.4 mg, about 16.6 mg, about 16.8 mg, about17 mg, about 17.2 mg, about 17.4 mg, about 17.6 mg, about 17.8 mg, about18 mg, about 18.2 mg, about 18.4 mg, about 18.6 mg, about 18.8 mg, about19 mg, about 19.2 mg, about 19.4 mg, about 19.6 mg, about 19.8 mg, about20 mg, about 20.2 mg, about 20.4 mg, about 20.6 mg, about 20.8 mg, about21 mg, about 21.2 mg, about 21.4 mg, about 21.6 mg, about 21.8 mg, about22 mg, about 22.2 mg, about 22.4 mg, about 22.6 mg, about 22.8 mg, about23 mg, about 23.2 mg, about 23.4 mg, about 23.6 mg, about 23.8 mg, about24 mg, about 24.2 mg, about 24.4 mg, about 24.6 mg, about 24.8 mg, orabout 25 mg. In another embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is in the range of about 12 mg toabout 40 mg. In another embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is in the range of about 12 mg toabout 25 mg. In another embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is in the range of about 12 mg toabout 15 mg. In another embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is in the range of about 5 mg toabout 12 mg. In a specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 22 mg. In anotherspecific embodiment of the foregoing, the amount of 4-aminopyridine inthe compressed core is about 16.5 mg. In another specific embodiment ofthe foregoing, the amount of 4-aminopyridine in the compressed core isabout 11 mg. In a specific embodiment, the sustained release tablet asdisclosed herein is orally administered once daily to an adult patient,wherein the compressed core of the sustained release tablet comprises4-aminopyridine in an amount in the range of about 16 mg to about 22 mg.In another specific embodiment, the sustained release tablet asdisclosed herein is orally administered once daily to an adolescentpatient, wherein the compressed core of the sustained release tabletcomprises 4-aminopyridine in an amount in the range of about 12 mg toabout 22 mg. In another specific embodiment, the sustained releasetablet as disclosed herein is orally administered once daily to a childpatient of age 6-12, wherein the compressed core of the sustainedrelease tablet comprises 4-aminopyridine in an amount in the range ofabout 4 mg to about 13 mg.

In a specific embodiment, the sustained release tablet as disclosedherein is orally administered once daily to a pediatric patient, whereinthe compressed core of the sustained release tablet comprises4-aminopyridine in an amount in the range of about 4 mg to about 13 mg.In a specific embodiment of the foregoing, the amount of 4-aminopyridinein the compressed core is in the range of about 4 mg to about 11 mg,about 4 mg to about 9 mg, about 4 mg to about 7 mg, about 4 mg to about5 mg, about 5 mg to about 13 mg, about 5 mg to about 11 mg, about 5 mgto about 9 mg, about 5 mg to about 7 mg, about 7 mg, to about 13 mg,about 7 mg to about 11 mg, about 7 mg to about 9 mg, about 9 mg to about13 mg, about 9 mg to about 11 mg, or about 11 mg to about 13 mg. Inanother specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 6 mg, about 6.5 mg,about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, or about12 mg. In another specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 11 mg. In anotherspecific embodiment of the foregoing, the amount of 4-aminopyridine inthe compressed core is about 8 mg. In one embodiment, the pediatric doseis half of the adult dose. For example, if the amount of 4-aminopyridinein the compressed core orally administered once daily to an adultpatient is about 22 mg, the amount of 4-aminopyridine in the compressedcore orally administered to a pediatric patient is about 11 mg.

In one embodiment, the sustained release tablet as disclosed herein isorally administered once daily to a patient with renal impairment,wherein the compressed core of the sustained release tablet comprises4-aminopyridine in an amount in the range of about 4 mg to about 20 mg.In a specific embodiment of the foregoing, the amount of 4-aminopyridinein the compressed core is about 6 mg to about 20 mg, about 6 mg to about16 mg, about 6 mg to about 12 mg, about 6 mg to about 18 mg, about 8 mgto about 20 mg, about 8 mg to about 16 mg, about 8 mg to about 12 mg,about 10 mg to about 20 mg, about 10 mg to about 16 mg, about 10 mg toabout 12 mg, about 12 mg to about 20 mg, about 12 mg to about 16 mg,about 14 mg to about 20 mg, about 14 mg to about 16 mg, or about 16 mgto about 20 mg. In a specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 7 mg to about 9 mg. Inanother specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 11 mg to about 13 mg. Inanother specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 12 mg to about 15 mg. Inanother specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 15 mg to about 17 mg. Inanother specific embodiment of the foregoing, the amount of4-aminopyridine in the compressed core is about 7 mg, about 7.5 mg,about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about15.5 mg, about 16 mg, about 16.5 mg or about 17 mg. In a specificembodiment, the sustained release tablet of any of the foregoingembodiments is orally administered once daily to a patient with mild ormoderate renal impairment.

In one embodiment, the sustained release 4-aminopyridine tablet asdisclosed herein is orally administered once daily to a patient with norenal impairment. In one embodiment, the patient is classified as havingno renal impairment when the patient has an estimated glomerularfiltration rate of ≥90 mL/min/1.73 m². In one embodiment, the patient isclassified as having no renal impairment when the patient has acreatinine clearance value of ≥90 mL/min.

Preferably, a sustained release 4-aminopyridine tablet as disclosedherein, upon oral administration to human subjects does not result insubstantial dose dumping in the presence of food. In one embodiment, thesustained release 4-aminopyridine tablet, upon oral administration tohuman subjects does not result in clinically relevant differences inpharmacokinetic parameters such as AUC or C_(max) between the fed orfasted conditions when administered to human subjects in fed and fastedconditions. In one embodiment, a human subject having consumed ahigh-fat high-calorie meal before oral administration (as described inGuidance for Industry, Food-Effect Bioavailability and FedBioequivalence Studies, U.S. Department of Health and Human Services,Food and Drug Administration, December 2002) is considered to be in afed state. In one embodiment, a human subject observing an overnightfast of at least 10 h is considered to be in a fasted state.

In a specific embodiment, a sustained release 4-aminopyridine tablet asdisclosed herein, upon oral administration to human subjects in a fastedstate, provides one or more of the following pharmacokinetic parameters:(a) a mean plasma 4-aminopyridine C_(max) in the range of about 14.74ng/mL to about 20.66 ng/mL; (b) a median plasma 4-aminopyridine T_(max)in the range of about 3 h to about 14 h; (c) a mean plasma4-aminopyridine AUC₀₋₃₆ in the range of about 232 ng·h/mL to about 434ng·h/mL; and (d) a mean plasma 4-aminopyridine AUC_(0-∞) in the range ofabout 230 ng·h/mL to about 472 ng·h/mL. In a specific embodiment of theforegoing, the amount of 4-aminopyridine in the sustained release tabletis about 22 mg. AUC₀₋₃₆ is the area under the curve for 0-36 h. In apreferred embodiment, the sustained release tablet which ischaracterized by the foregoing pharmacokinetic parameters is a tablet inwhich 4-aminopyridine is present only in the compressed core (whichtablet can be the final oral dosage form of a tablet that does not havean immediate release drug overcoat, or can be the tablet that has notyet been coated with the drug overcoat in an embodiment where the finaloral dosage form will have a drug overcoat).

In another specific embodiment, a sustained release 4-aminopyridinetablet as disclosed herein, upon oral administration to human subjectsin a fed state, provides one or more of the following pharmacokineticparameters: (a) a mean plasma 4-aminopyridine C_(max) in the range ofabout 13.73 ng/mL to about 24.07 ng/mL; (b) a median plasma4-aminopyridine T_(max) in the range of about 6 h to about 21 h; (c) amean plasma 4-aminopyridine AUC₀₋₃₆ in the range of about 216 ng·h/mL toabout 472 ng·h/mL; and (d) a mean plasma 4-aminopyridine AUC_(0-∞) inthe range of about 218 ng·h/mL to about 490 ng·h/mL. In a specificembodiment of the foregoing, the amount of 4-aminopyridine in thesustained release tablet is about 22 mg. In a preferred embodiment, thesustained release tablet which is characterized by the foregoingpharmacokinetic parameters is a tablet in which 4-aminopyridine ispresent only in the compressed core (which tablet can be the final oraldosage form of a tablet that does not have an immediate release drugovercoat, or can be the tablet that has not yet been coated with thedrug overcoat in an embodiment where the final oral dosage form willhave a drug overcoat).

5.3 Combination Therapy

In certain embodiments, the sustained release 4-aminopyridine tablet asdisclosed herein may be orally administered in combination with one ormore additional medicaments. Such combination therapy may be achieved byway of the simultaneous, sequential, or separate dosing of theindividual components of the treatment. In one embodiment, thecombination therapy is achieved by way of separate dosing of thesustained release 4-aminopyridine tablet and the other medicament.

In certain embodiments, the other medicament is a therapeutic agenteffective for the treatment of multiple sclerosis. In specificembodiments, the other medicament is selected from a group consistingof, but not limited to, AVONEX (interferon beta-1a), REBIF (interferonbeta-1a), BETASERON and EXTAVIA (interferon beta-1b), COPAXONE(glatiramer acetate), NOVANTRONE (mitoxantrone), TYSABRI (natalizumab),AUBAGIO (teriflunomide), GILENYA (fingolimod), LEMTRADA (alemtuzumab),PLEGRIDY (peginterferon beta-1a), TECFIDERA (dimethyl fumarate),ocrelizumab, prednisone, prednisolone, methylprednisolone,betamethasone, and dexamethasone.

In certain embodiments, the other medicament is a therapeutic agentintended for the prophylaxis of stroke. In specific embodiments, theother medicament is selected from the group consisting of, but notlimited to, anti-coagulant agents (e.g. aspirin, clopidogrel, etc.) andanti-hypertensive agents.

6 EXAMPLES

Certain embodiments provided herein are illustrated by the followingnon-limiting examples.

6.1 Example 1: Preparation of Sustained Release 4-Aminopyridine Tablets

6.1.1 Dispensing, Sifting and Blending

4-Aminopyridine (110.0 g), Kollidon SR Polymer (550.0 g), PolyethyleneOxide, NF (Sentry Polyox WSR 303) (330.0 g), and Dibasic CalciumPhosphate Dihydrate, USP/NF (1188 g) were sifted through a 30 mesh handscreen into a container double-lined with polyethylene bags. The siftedpowders obtained above were placed in an 8 quart V-Blender, and blendedfor 10 minutes. To this blended mixture was added Magnesium Stearate, NFNon-Bovine Hyqual (22.0 g) that was sifted through a 20 mesh handscreen. The entire mixture was blended for additional 5 minutes, andthen the blend was discharged into a container lined with twopolyethylene bags after performing content uniformity and physicaltesting on the final blend.

6.1.2 Tableting

The completed blend from above was fed into a tablet press hopper. Arotary tablet press (power assisted) was set up with a tablet dedusterand metal detector in-line. Batch set-up parameters were then determinedto achieve tablets a target weight of 440 mg (individual range 407-473mg).

The blend was then compressed using a Compact-19 Tablet Press withTooling Set No. 138 to furnish the desired core tablets, whileperforming checks on individual tablet weight, mean tablet weight,hardness, thickness, appearance and friability at defined times duringthe compression run. The weight of the desired tablets was within+/−7.5% of theoretical tablet weight of 440 mg (i.e., within 407.0-473.0mg).

6.1.3 Coating and Curing

Purified Water (686.0 g) was weighed into a suitable solution tank. ThePurified Water was mixed with Ethylcellulose Dispersion Type B, NF(Surelease E-7-19040, Clear) (1030 g) while stirring using an overheadmixer with a suitable impeller. Mixing was continued for at least 15minutes with low to moderate agitation, while ensuring there are novisual signs for any lumps, foam, settling, etc. prior to coating.

The core tablets prepared in Section 6.1.2 were loaded into a LabCoat MXtablet coater equipped with a 15″ pan, a peristaltic pump with newtubing (Maserflex Pt/Si Size 14) and a single spray gun. The tabletswere pre-warm for approximately 10 minutes by jogging the pan with thefan and heater on at 50° C. After setting the Supply Temperature totarget 60° C., the above prepared film-coat was applied in a controlledmanner to the pre-warmed core tablets in the Labcoat MX to approximately9% weight gain (i.e., 39.6 mg). The coated tablets thus formed were thensubjected to a curing step by drying them at 55° C. for 1 hour and thenallowed to cool for at least 5 minutes to a target exhaust temperatureof approximately 25-30° C. while jogging the pan. The tablets were thendischarged into a suitable container lined with two polyethylene bags toafford the final coated tablets.

Table 1 provides the amounts and weight percentages of ingredientspresent in the sustained release tablet prepared using the methoddescribed above.

TABLE 1 Composition of sustained release tablets containing 22 mg4-aminopyridine and 9% ethylcellulose coat by weight of the compressedcore % w/w of Amount per Ingredient compressed core tablet (mg)Compressed Core 4-aminopyridine 5.0 22.0 KOLLIDON ® SR 25.0 110.0Polyethylene oxide 15.0 66.0 (Sentry Polyox WSR 303) Dibasic calciumphosphate 54.0 237.6 dihydrate Magnesium stearate 1.0 4.4 Weight ofCompressed Core 100 440 Functional Coating Ethylcellulose Dispersion 939.6 Type B

Thus, for the sustained release tablet of Example 1, containing 22 mg4-aminopyridine (i.e., 5% w/w of the compressed cored) and 9%ethylcellulose coat by weight of the compressed core, the ratio of theamount of the ethylcellulose coat to the amount of 4-aminopyridine is1.8:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core (i.e., 9%), and the amount of4-aminopyridine is the weight percentage of 4-aminopyridine by weight ofthe compressed core (i.e. 5%).

Similarly, for the sustained release tablet of Example 1, containing 22mg 4-aminopyridine (i.e., 5% w/w of the compressed cored) and 9%ethylcellulose coat by weight of the compressed core, the ratio of theamount of the ethylcellulose coat to the amount of 4-aminopyridine inthe compressed core is about 0.4:1; wherein for calculating said ratio,the amount of the ethylcellulose coat is the weight percentage of theethylcellulose coat by weight of the compressed core (i.e., 9%), and theamount of 4-aminopyridine is the weight in milligrams of 4-aminopyridine(i.e., 22 mg).

The dissolution profile of the sustained release tablet in Example 1 isshown in FIG. 1. The dissolution profile was generated using theconditions shown in Table 2 below.

TABLE 2 Dissolution profile parameters Apparatus USP Type II (Paddles)Paddle Speed 50 RPM Dissolution Medium 50 mM Phosphate Buffer, pH 6.8Dissolution Medium 37.0 ± 0.5° C. Temperature Sampling Time Profile 1,2, 4, 6, 8, 10, 12, 14, 18, and 24 hours Vessel Volume 900 mL UVWavelength 262 nm Cell 1 mm, quartz Sinkers QLA, 2S

At each sampling time point, a 10 mL sample aliquot was removed fromeach vessel and collected in a test tube. Each sample aliquot wasfiltered through a 0.45 μm nylon syringe filter. The first 2 mL of thefiltrate was discarded, and the remaining filtrate was collected for UVanalysis.

To test alcohol dose dumping, dissolution for 2 hours was performed byemploying 0.1 N HCl containing 40% alcohol (ethanol) as a dissolutionmedium. The results are shown in FIG. 2.

6.2 Example 2: Sustained Release Tablets Containing 22 mg4-Aminopyridine and Coated to 8%, 9%, and 10% weight gain

Core tablets (i.e., compressed cores) containing 22 mg 4-aminopyridinewere prepared using the formulation described in Table 1 and the methoddescribed in Example 1, Sections 6.1.1 and 6.1.2. These core tabletswere coated with an aqueous Ethylcellulose Dispersion Type B (SureleaseE-7-19040, Clear) coat to approximately 8% and 10% weight gain,following the procedure described in Example 1, Section 6.1.3. Acomparison of the dissolution profiles (generated using the parametersshown in Table 2) of the sustained release tablets containing 22 mg4-aminopyridine, coated with an aqueous Ethylcellulose Dispersion Type Bcoat to approximately 8% (Example 2), 9% (tablets generated pursuant toExample 1), and 10% (Example 2) weight gain, is shown in FIG. 3 andTable 3.

TABLE 3 Dissolution profiles of sustained release tablets containing 22mg 4-aminopyridine, coated to 8%, 9%, and 10% weight gain. % 4APreleased Coat % 0 h 1 h 2h 4 h 6 h 8 h 10 h 12 h 14 h 18 h 24 h 8% 0 2 921 37 52 64 74 82 90 99 9% 0 2 8 21 36 50 62 72 80 90 97 10%  0 2 8 2035 48 60 71 78 88 97

6.3 Example 3: Preparation of Sustained Release Tablets Containing 16.5mg 4-Aminopyridine

Sustained release tablets containing 16.5 mg 4-aminopyridine wereprepared using the method described in Example 1, except using theamounts and weight percentages of ingredients shown in Table 4.

TABLE 4 Composition of sustained release tablets containing 16.5 mg4-aminopyridine and 6% ethylcellulose coat by weight of the compressedcore % w/w of Amount per Ingredient compressed core tablet (mg)Compressed Core 4-aminopyridine 3.75 16.5 KOLLIDON ® SR 25.0 110.0Polyethylene oxide 15.0 66.0 (Sentry Polyox WSR 303) Dibasic calciumphosphate 55.25 243.1 dihydrate Magnesium stearate 1.0 4.4 Weight ofCompressed Core 100 440 Functional Coating Ethylcellulose Dispersion 626.4 Type B

Thus, for the sustained release tablet containing 16.5 mg4-aminopyridine (i.e., 3.75% w/w of the compressed cored) and 6%ethylcellulose coat by weight of the compressed core, the ratio of theamount of the ethylcellulose coat to the amount of 4-aminopyridine is1.6:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core (i.e., 6%), and the amount of4-aminopyridine is the weight percentage of 4-aminopyridine by weight ofthe compressed core (i.e. 3.75%).

Similarly, for the sustained release tablet containing 16.5 mg4-aminopyridine (i.e., 3.75% w/w of the compressed cored) and 6%ethylcellulose coat by weight of the compressed core, the ratio of theamount of the ethylcellulose coat to the amount of 4-aminopyridine inthe compressed core is about 0.35:1; wherein for calculating said ratio,the amount of the ethylcellulose coat is the weight percentage of theethylcellulose coat by weight of the compressed core (i.e., 6%), and theamount of 4-aminopyridine is the weight in milligrams of 4-aminopyridine(i.e., 16.5 mg).

In addition, the core tablets prepared using the formulation describedin Table 4 were coated with an aqueous Ethylcellulose Dispersion Type B(Surelease E-7-19040, Clear) coat to approximately 5% and 7% weightgain. A comparison of the dissolution profiles (generated using theparameters shown in Table 2) of the sustained release tablets containing16.5 mg 4-aminopyridine, coated with an aqueous EthylcelluloseDispersion Type B coat to approximately 5%, 6%, and 7% weight gain, isshown in FIG. 4 and Table 5.

TABLE 5 Dissolution profiles of sustained release tablets containing16.5 mg 4-aminopyridine, coated to 5%, 6%, and 7% weight gain. % 4APreleased Coat % 0 h 1 h 2 h 4 h 6 h 8 h 10 h 12 h 14 h 18 h 24 h 5% 0 616 35 51 63 73 81 87 94 98 6% 0 5 14 30 46 59 69 77 84 91 96 7% 0 3 1024 40 53 64 74 81 89 98

6.4 Example 4: Preparation of Sustained Release Tablets Containing 22 mg4-Aminopyridine and Coated to 5% weight gain

6.4.1 Dispensing, Sifting and Blending

4-Aminopyridine (5000.0 g), Kollidon SR Polymer (25000.0 g),Polyethylene Oxide, NF (Sentry Polyox WSR 303) (15000.0 g), and DibasicCalcium Phosphate Dihydrate, USP/NF (54000.0 g) were sifted through a 30mesh hand screen into a container double-lined with polyethylene bags.The sifted powders obtained above were placed in an 8.5 cu foot tote,and blended for 5 minutes. To this blended mixture was added MagnesiumStearate, NF Non-Bovine Hyqual (1000.0 g) that was sifted through a 20mesh hand screen. The entire mixture was blended for additional 19minutes, and then the blend was discharged into a container lined withtwo polyethylene bags after performing blend uniformity and physicaltesting on the final blend.

6.4.2 Tableting

The completed blend from above was fed into a tablet press hopper. Asingle rotary tablet press (power assisted) was set up with a tabletdeduster and metal detector in-line. Batch set-up parameters were thendetermined to achieve tablets a target weight of 440 mg (individualrange 407-473 mg).

The blend was then compressed using a Fette 1200i Tablet Press withTooling Set No. 138 to furnish the desired core tablets, whileperforming checks on individual tablet weight, mean tablet weight,hardness, thickness, appearance and friability at defined times duringthe compression run. The weight of the desired tablets was within+/−7.5% of theoretical tablet weight of 440 mg (i.e., within 407.0-473.0mg).

6.4.3 Coating and Curing

Purified Water (31200.0 g) was weighed into a suitable solution tank.The Purified Water was mixed with Ethylcellulose Dispersion Type B, NF(Surelease E-7-19040, Clear) (46800 g) while stirring using an overheadmixer with a suitable impeller. Mixing was continued for at least 15minutes with low to moderate agitation, while ensuring there are novisual signs for any lumps, foam, settling, etc. prior to coating.

The core tablets prepared in the above section were loaded into a O'Harafastcoat48 tablet coater equipped with a 48″ pan, a peristaltic pumpwith a new tubing (Maserflex Pt/Si Size 35) and 4 spray guns. Thetablets were pre-warmed for approximately 10 minutes by jogging the panwith the fan and heater on at 50° C. After setting the SupplyTemperature to target 65° C., the above prepared film-coat was appliedin a controlled manner to the pre-warmed core tablets in the O'Harafastcoat48 tablet coater to approximately 5% weight gain (i.e., 22.0mg). The coated tablets thus formed were then subjected to a curing stepby drying them at 55° C. for 1 hour and then allowed to cool for atleast 5 minutes to a target exhaust temperature of approximately 25-30°C. while jogging the pan. The tablets were then discharged into asuitable container lined with two polyethylene bags to afford the finalcoated tablets.

Table 6 provides the amounts and weight percentages of ingredientspresent in the sustained release tablet prepared using the methoddescribed above:

TABLE 6 Composition of sustained release tablets containing 22 mg4-aminopyridine and 5% ethylcellulose coat by weight of the compressedcore % w/w of Amount per Ingredient compressed core tablet (mg)Compressed Core 4-aminopyridine 5.0 22.0 KOLLIDON ® SR 25.0 110.0Polyethylene oxide 15.0 66.0 (Sentry Polyox WSR 303) Dibasic calciumphosphate 54.0 237.6 dihydrate Magnesium stearate 1.0 4.4 Weight ofCompressed Core 100 440 Functional Coating Ethylcellulose Dispersion 522.0 Type B

The dissolution profile (generated using the conditions shown in Table2) of the sustained release tablet in Example 4 is shown in FIG. 5.

6.5 Example 5: Pharmacokinetic Studies

A study was conducted evaluating the effect of food on thepharmacokinetics of the prototype 22 mg 4-aminopyridine sustainedrelease tablet prepared as described in Example 1, following oraladministration of a single dose in healthy human subjects. In the study,subjects observed an overnight fast of at least 10 hours prior todosing. The following morning, a single dose was orally administeredwith 240 mL water. The dose was administered on an empty stomach in thefasted condition (N=20) and following a standard high fat-high contentmeal (see, Guidance for Industry: Food-Effect Bioavailability and FedBioequivalence Studies, Food and Drug Administration, Center for DrugEvaluation and Research (CDER), December 2002) in the fed condition(N=20).

A summary of the pharmacokinetic parameters for dalfampridine followingoral administration of the 22 mg prototype tablet of Example 1 inhealthy human subjects in fed (N=20) and fasted (N=20) states ispresented in Table 7. Mean C_(max) and AUC values were comparablefollowing administration in both fed and fasted states.

Following administration of the prototype formulation in the fed state,absorption was slightly delayed than that of the fasted state, mediant_(max) of 12.0 and 7.50 hours, respectively. There were no othernotable differences in the pharmacokinetics of the prototype formulationwhen administered in the fed versus the fasted state.

TABLE 7 Summary of Pharmacokinetic Parameters of Dalfampridine FollowingAdministration of a Single Oral Dose of the 22 mg 4-AminopyridineSustained Release Tablet of Example 1 in Healthy Human Subjects in Fedor Fasted States Prototype-Fed Prototype-Fasted PharmacokineticArithmetic Arithmetic Parameter Mean ± SD Mean ± SD (units) (N = 20) (N= 20) C_(max) (ng/mL) 18.9 ± 5.17 17.7 ± 2.96 AUC_(0-last) (ng · hr/mL)342 ± 131 330 ± 104 AUC₀₋₃₆ (ng · hr/mL) 344 ± 128 333 ± 101 AUC_(0-∞)(ng · hr/mL) 354 ± 136 351 ± 121 t_(max) (hr)^(a) 12.0 [6.0, 21.0] 7.50[3.0, 14.0] t_(lag) (hr)^(a) 1.0 [0, 2.0]   0.50 [0, 1.0]   λ_(z)(1/hr)^(b)  0.176 ± 0.0331  0.172 ± 0.0551 t_(1/2) (hr)  4.1 ± 0.87  4.7± 2.30 ^(a)Median [min, max] reported for t_(max) and t_(lag); t_(lag)is defined as time prior to the first measurable (non-zero) plasmaconcentration ^(b)λ_(z) is defined as apparent elimination rate constant

The mean plasma concentrations over time are shown in FIG. 6, whichdemonstrates that sustained plasma levels are achieved over a 24-hourperiod with a single dose. These sustained plasma levels demonstratefeasibility of once-daily dosing.

INCORPORATION BY REFERENCE

Various references such as patents, patent applications, andpublications are cited herein, the disclosures of which are herebyincorporated by reference herein in their entireties.

1. A sustained release tablet comprising: (a) a compressed core, saidcompressed core comprising 4-aminopyridine, a polyethylene oxide with amolecular weight between about 1,000,000 and 10,000,000, and a mixturecomprising polyvinyl acetate and polyvinyl pyrrolidone; and (b) anamount of an ethylcellulose coat surrounding said compressed core, saidamount of the ethylcellulose coat being in the range of about 5% w/w toabout 10% w/w of the compressed core.
 2. The sustained release tablet ofclaim 1, wherein said mixture further comprises one or morepharmaceutically acceptable excipients.
 3. The sustained release tabletof claim 1, wherein said mixture comprises 70-90% polyvinyl acetate and15-20% polyvinyl pyrrolidone.
 4. The sustained release tablet of any ofclaims 1-3, wherein said mixture further comprises a surfactant.
 5. Thesustained release tablet of claim 4, wherein said mixture furthercomprises silica.
 6. The sustained release tablet of any of claims 1-5,wherein said mixture consists of about 80% polyvinyl acetate, about 19%polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2%silica.
 7. The sustained release tablet of any of claims 1-6, whereinthe compressed core further comprises a filler and a lubricant.
 8. Thesustained release tablet of claim 7, wherein the filler is dibasiccalcium phosphate dihydrate, and the lubricant is magnesium stearate. 9.The sustained release tablet of any of claims 1-8, wherein thepolyethylene oxide has a molecular weight between 4,000,000 and8,000,000.
 10. The sustained release tablet of any of claims 1-8,wherein the polyethylene oxide has a molecular weight of 7,000,000. 11.The sustained release tablet of any of claims 1-10, wherein the totalamount of the 4-aminopyridine in the tablet is in the range of about 1%w/w to about 10% w/w of the sustained release tablet.
 12. The sustainedrelease tablet of any of claims 1-10, wherein the total amount of the4-aminopyridine in the tablet is in the range of about 1% w/w to about10% w/w of the compressed core.
 13. A sustained release tabletcomprising: (a) a compressed core, wherein said compressed corecomprises: (i) 4-aminopyridine, (ii) a polyethylene oxide with amolecular weight between about 1,000,000 and 10,000,000, (iii) a mixtureconsisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,(iv) dibasic calcium phosphate dihydrate, and (v) magnesium stearate;and (b) an amount of an ethylcellulose coat surrounding said compressedcore, said amount of the ethylcellulose coat being in the range of about5% w/w to about 10% w/w of the compressed core, wherein the amount of4-aminopyridine is in the range of about 4% w/w to about 6% w/w of thecompressed core.
 14. The sustained release tablet of any of claims 1-13,wherein the amount of the ethylcellulose coat surrounding the compressedcore is about 9% w/w of the compressed core.
 15. A sustained releasetablet comprising: (a) a compressed core, said compressed corecomprising 4-aminopyridine, a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000, and a mixture comprisingpolyvinyl acetate and polyvinyl pyrrolidone; and (b) an amount of anethylcellulose coat surrounding said compressed core, said amount of theethylcellulose coat being in the range of about 5% w/w to about 7% w/wof the compressed core.
 16. The sustained release tablet of claim 15,wherein the amount of 4-aminopyridine is in the range of about 3% w/w toabout 5% w/w of the compressed core and the amount of the ethylcellulosecoat surrounding the compressed core is about 6% w/w of the compressedcore.
 17. The sustained release tablet of any of claims 1-16, whereinthe amount of 4-aminopyridine in the compressed core is in the range ofabout 12 mg to about 25 mg.
 18. The sustained release tablet of any ofclaims 1-17, wherein the amount of 4-aminopyridine in the compressedcore is in the range of about 20 mg to about 25 mg.
 19. The sustainedrelease tablet of any of claims 1-18, wherein the amount of4-aminopyridine in the compressed core is about 22 mg.
 20. The sustainedrelease tablet of any of claims 1-19, wherein the amount of4-aminopyridine in the compressed core is about 16.5 mg.
 21. Thesustained release tablet of any of claims 1-16, wherein the amount of4-aminopyridine in the compressed core is in the range of about 5 mg toabout 12 mg.
 22. A sustained release tablet comprising: (a) a compressedcore, wherein said compressed core comprises: (i) 4-aminopyridine,wherein the amount of 4-aminopyridine is in the range of about 4% w/w toabout 6% w/w of the compressed core; (ii) a polyethylene oxide with amolecular weight between about 1,000,000 and 10,000,000, wherein theamount of the polyethylene oxide is in the range of about 10% w/w toabout 20% w/w of the compressed core; (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica, wherein the amount ofthe mixture is in the range of about 20% w/w to about 30% w/w of thecompressed core; (iv) dibasic calcium phosphate dihydrate, wherein theamount of dibasic calcium phosphate dihydrate is in the range of about50% w/w to about 60% w/w of the compressed core; and (v) magnesiumstearate, wherein the amount of magnesium stearate is in the range ofabout 0.7% w/w to about 1.3% w/w of the compressed core; and (b) anamount of an ethylcellulose coat surrounding said compressed core, saidamount of the ethylcellulose coat being in the range of about 5% w/w toabout 10% w/w of the compressed core.
 23. A sustained release tabletcomprising: (a) a compressed core, wherein said compressed corecomprises: (i) 4-aminopyridine, wherein the amount of 4-aminopyridine isin the range of about 4% w/w to about 6% w/w of the compressed core;(ii) a polyethylene oxide with a molecular weight of 7,000,000, whereinthe amount of the polyethylene oxide is about 15% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is about 25% w/w ofthe compressed core; (iv) dibasic calcium phosphate dihydrate, whereinthe amount of dibasic calcium phosphate dihydrate is about 54% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is about 1% w/w of the compressed core; and (b) anamount of an ethylcellulose coat surrounding said compressed core, saidamount of the ethylcellulose coat being about 9% w/w of the compressedcore.
 24. The sustained release tablet of claim 23, wherein the amountof 4-aminopyridine is about 22 mg.
 25. A sustained release tabletcomprising: (a) a compressed core, wherein said compressed corecomprises: (i) 4-aminopyridine, wherein the amount of 4-aminopyridine isin the range of about 3% w/w to about 5% w/w of the compressed core;(ii) a polyethylene oxide with a molecular weight between about1,000,000 and 10,000,000, wherein the amount of the polyethylene oxideis in the range of about 10% w/w to about 20% w/w of the compressedcore; (iii) a mixture consisting of about 80% polyvinyl acetate, about19% polyvinyl pyrrolidone, about 0.8% sodium lauryl sulfate, and about0.2% of silica, wherein the amount of the mixture is in the range ofabout 20% w/w to about 30% w/w of the compressed core; (iv) dibasiccalcium phosphate dihydrate, wherein the amount of dibasic calciumphosphate dihydrate is in the range of about 50% w/w to about 60% w/w ofthe compressed core; and (v) magnesium stearate, wherein the amount ofmagnesium stearate is in the range of about 0.7% w/w to about 1.3% w/wof the compressed core; and (b) an amount of an ethylcellulose coatsurrounding said compressed core, said amount of the ethylcellulose coatbeing in the range of about 5% w/w to about 7% w/w of the compressedcore.
 26. A sustained release tablet comprising: (a) a compressed core,wherein said compressed core comprises: (i) 4-aminopyridine, wherein theamount of 4-aminopyridine is in the range of about 3% w/w to about 5%w/w of the compressed core; (ii) a polyethylene oxide with a molecularweight of 7,000,000, wherein the amount of the polyethylene oxide isabout 15% w/w of the compressed core; (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica, wherein the amount ofthe mixture is about 25% w/w of the compressed core; (iv) dibasiccalcium phosphate dihydrate, wherein the amount of dibasic calciumphosphate dihydrate is about 55% w/w of the compressed core; and (v)magnesium stearate, wherein the amount of magnesium stearate is about 1%w/w of the compressed core; and (b) an amount of an ethylcellulose coatsurrounding said compressed core, said amount of the ethylcellulose coatbeing about 6% w/w of the compressed core.
 27. The sustained releasetablet of claim 26, wherein the amount of 4-aminopyridine is about 16.5mg.
 28. A sustained release tablet comprising: (a) a compressed core,said compressed core comprising 4-aminopyridine, a polyethylene oxidewith a molecular weight between about 1,000,000 and 10,000,000, and amixture comprising polyvinyl acetate and polyvinyl pyrrolidone; and (b)an amount of an ethylcellulose coat surrounding said compressed core,wherein the ratio of the amount of the ethylcellulose coat to the amountof 4-aminopyridine in the compressed core is in the range of about 0.5:1to about 3:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core, and the amount of 4-aminopyridine isthe weight percentage of 4-aminopyridine by weight of the compressedcore.
 29. A sustained release tablet comprising: (a) a compressed core,said compressed core comprising 4-aminopyridine, a polyethylene oxidewith a molecular weight between about 1,000,000 and 10,000,000, and amixture comprising polyvinyl acetate and polyvinyl pyrrolidone; and (b)an amount of an ethylcellulose coat surrounding said compressed core,wherein the ratio of the amount of the ethylcellulose coat to the amountof 4-aminopyridine in the compressed core is in the range of about 0.1:1to about 0.7:1; wherein for calculating said ratio, the amount of theethylcellulose coat is the weight percentage of the ethylcellulose coatby weight of the compressed core, and the amount of 4-aminopyridine isthe weight in milligrams of 4-aminopyridine.
 30. The sustained releasetablet of any of claims 1-29, wherein the sustained release tablet isthe product of a process comprising a curing step after coating thecompressed core with ethylcellulose, and wherein said curing stepcomprises heating the coated compressed core to a temperature above 23°C. for a period of time of at least 15 minutes.
 31. The sustainedrelease tablet of claim 30, wherein said curing step comprises exposingthe coated compressed core to a temperature in the range of 50-60° C.for a period of time of at least 1 hour.
 32. The sustained releasetablet of any of claims 1-31, wherein the sustained release tablet doesnot further comprise an immediate release drug overcoat containing4-aminopyridine.
 33. The sustained release tablet of any of claims 1-32,wherein the sustained release tablet provides a zero-order ornear-zero-order release of the 4-aminopyridine.
 34. The sustainedrelease tablet of claim 33, wherein the release is zero-order.
 35. Thesustained release tablet of any of claims 1-34, wherein the sustainedrelease tablet is suitable for once daily oral administration.
 36. Thesustained release tablet of any of claims 1-35, wherein the sustainedrelease tablet comprises an amount of 4-aminopyridine that istherapeutically effective over a period of 24 hours upon oraladministration to a human patient.
 37. The sustained release tablet ofany of claims 1-36, wherein the release of the 4-aminopyridine, uponsubjecting the tablet to an in vitro dissolution test employing 50 mMPhosphate Buffer, pH 6.8 as dissolution medium, is as follows: withinthe first 2 hours after the start of the test at most 30% w/w of thetotal amount of the 4-aminopyridine contained in the sustained releasetablet is released.
 38. The sustained release tablet of claim 37,wherein the release of the 4-aminopyridine is as follows: within thefirst 24 hours after the start of the test at least 80% w/w of the totalamount of the 4-aminopyridine contained in the sustained release tabletis released.
 39. The sustained release tablet of any of claims 1-31,wherein the sustained release tablet further comprises an immediaterelease drug overcoat containing 4-aminopyridine.
 40. A method of makinga sustained release tablet comprising 4-aminopyridine, which methodcomprises: (a) forming a compressed core comprising (i) 4-aminopyridine,(ii) a polyethylene oxide with a molecular weight between about1,000,000 and 10,000,000, (iii) a mixture comprising polyvinyl acetateand polyvinyl pyrrolidone; (iv) dibasic calcium phosphate dihydrate, and(v) magnesium stearate; (b) coating the compressed core with an amountof ethylcellulose to form a coated compressed core, said amount of theethylcellulose coat being in the range of about 5% w/w to about 10% w/wof the compressed core; and (c) curing the coated compressed core byexposing it to a temperature in the range of 40-70° C. for a period oftime of at least 1 hour.
 41. The method of claim 40, wherein forming thecompressed core comprises: (a) blending the 4-aminopyridine,polyethylene oxide, the mixture comprising polyvinyl acetate andpolyvinyl pyrrolidone, and dibasic calcium phosphate dihydrate to form ablended mixture; (b) adding magnesium stearate to the blended mixture toform a new blend; and (c) compressing the new blend to form a compressedcore.
 42. The method of claim 40 or 41, wherein said mixture consists ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% silica.
 43. The method of any ofclaims 40-42, wherein the polyethylene oxide has a molecular weightbetween 4,000,000 and 8,000,000.
 44. The method of any of claims 40-43,wherein the polyethylene oxide has a molecular weight of 7,000,000. 45.The method of any of claims 40-44, wherein the coating comprisesapplying an aqueous ethylcellulose dispersion to the compressed core.46. The method of any of claims 40-45, wherein the total amount of the4-aminopyridine in the sustained release tablet is in the range of about1% w/w to about 10% w/w of the sustained release tablet.
 47. The methodof any of claims 40-45, wherein the total amount of the 4-aminopyridinein the sustained release tablet is in the range of about 1% w/w to about10% w/w of the compressed core.
 48. A method of making a sustainedrelease tablet comprising 4-aminopyridine, which method comprises: (a)forming a compressed core comprising (i) 4-aminopyridine, wherein theamount of 4-aminopyridine is in the range of about 4% w/w to about 6%w/w of the compressed core, (ii) a polyethylene oxide with a molecularweight of 7,000,000, wherein the amount of the polyethylene oxide isabout 15% w/w of the compressed core, (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica, wherein the amount ofthe mixture is about 25% w/w of the compressed core; (iv) dibasiccalcium phosphate dihydrate, wherein the amount of dibasic calciumphosphate dihydrate is about 54% w/w of the compressed core; and (v)magnesium stearate, wherein the amount of magnesium stearate is about 1%w/w of the compressed core; (b) coating the compressed core with anamount of ethylcellulose to form a coated compressed core, said amountof the ethylcellulose coat being about 9% w/w of the compressed core;and (c) curing the coated compressed core by exposing it to atemperature in the range of 50-60° C. for a period of time of at least 1hour.
 49. The method of claim 48, wherein the amount of 4-aminopyridinein the compressed core is about 22 mg.
 50. A method of making asustained release tablet comprising 4-aminopyridine, which methodcomprises: (a) forming a compressed core comprising (i) 4-aminopyridine,wherein the amount of 4-aminopyridine is in the range of about 3% w/w toabout 5% w/w of the compressed core, (ii) a polyethylene oxide with amolecular weight of 7,000,000, wherein the amount of the polyethyleneoxide is about 15% w/w of the compressed core, (iii) a mixtureconsisting of about 80% polyvinyl acetate, about 19% polyvinylpyrrolidone, about 0.8% sodium lauryl sulfate, and about 0.2% of silica,wherein the amount of the mixture is about 25% w/w of the compressedcore; (iv) dibasic calcium phosphate dihydrate, wherein the amount ofdibasic calcium phosphate dihydrate is about 55% w/w of the compressedcore; and (v) magnesium stearate, wherein the amount of magnesiumstearate is about 1% w/w of the compressed core; (b) coating thecompressed core with an amount of ethylcellulose to form a coatedcompressed core, said amount of the ethylcellulose coat being about 6%w/w of the compressed core; and (c) curing the coated compressed core byexposing it to a temperature in the range of 50-60° C. for a period oftime of at least 1 hour.
 51. The method of claim 50, wherein the amountof 4-aminopyridine in the compressed core is about 16.5 mg.
 52. Themethod of any of claims 40-51, wherein the sustained release tablet issuitable for once daily oral administration.
 53. The method of any ofclaims 40-52, wherein the sustained release tablet comprises an amountof 4-aminopyridine that is therapeutically effective over a period of 24hours.
 54. A method of treating a neurological disorder in a patient inneed thereof comprising orally administering to the patient once dailythe sustained release tablet of any of claims 1-53.
 55. The method ofclaim 54, wherein the neurological disorder is multiple sclerosis orstroke.
 56. The method of claim 55, wherein the neurological disorder ismultiple sclerosis.
 57. The method of claim 56, wherein the neurologicaldisorder is a walking impairment associated with multiple sclerosis. 58.The method of claim 56, wherein the neurological disorder is aneurocognitive or neuropsychiatric impairment associated with multiplesclerosis.
 59. The method of claim 55, wherein the neurological disorderis stroke.
 60. The method of claim 59, wherein the neurological disorderis a sensorimotor impairment associated with stroke.
 61. The method ofclaim 59, wherein the neurological disorder is a walking impairmentassociated with stroke.
 62. The method of any of claims 54-61, whereinthe patient is a human patient.
 63. A sustained release tabletcomprising: (a) a compressed core, said compressed core comprising4-aminopyridine, a polyethylene oxide with a molecular weight betweenabout 1,000,000 and 10,000,000, and a mixture comprising polyvinylacetate and polyvinyl pyrrolidone; and (b) an amount of anethylcellulose coat surrounding said compressed core, said amount of theethylcellulose coat being in the range of about 8% w/w to about 10% w/wof the tablet, wherein said tablet is the product of a processcomprising a curing step after coating the compressed core withethylcellulose, and wherein said curing step comprises heating thecoated compressed core to a temperature above 23° C. for a period oftime of at least 15 minutes.
 64. A sustained release tablet comprising:(a) a compressed core, wherein said compressed core comprises: (i)4-aminopyridine, (ii) a polyethylene oxide with a molecular weightbetween about 1,000,000 and 10,000,000, (iii) a mixture consisting ofabout 80% polyvinyl acetate, about 19% polyvinyl pyrrolidone, about 0.8%sodium lauryl sulfate, and about 0.2% of silica, (iv) dibasic calciumphosphate dihydrate, and (v) magnesium stearate; and (b) an amount of anethylcellulose coat surrounding said compressed core, said amount of theethylcellulose coat being in the range of about 8% w/w to about 10% w/wof the tablet, wherein said sustained release tablet is the product of aprocess comprising a curing step after coating the compressed core withethylcellulose, wherein said curing step comprises exposing the coatedcompressed core to a temperature in the range of 50-60° C. for a periodof time of at least 1 hour, and wherein the amount of 4-aminopyridine isin the range of about 4% w/w to about 6% w/w of the sustained releasetablet.
 65. A method of making a sustained release tablet comprising4-aminopyridine, which method comprises: (a) forming a compressed corecomprising (i) 4-aminopyridine, (ii) a polyethylene oxide with amolecular weight between about 1,000,000 and 10,000,000, (iii) a mixturecomprising polyvinyl acetate and polyvinyl pyrrolidone; (iv) dibasiccalcium phosphate dihydrate, and (v) magnesium stearate; (b) coating thecompressed core with an amount of ethylcellulose to form a coatedcompressed core, said amount of the ethylcellulose coat being in therange of about 8% to about 10% w/w of the sustained release tablet; and(c) curing the coated compressed core by exposing it to a temperature inthe range of 40-70° C. for a period of time of at least 1 hour.
 66. Thesustained release tablet of claim 30, wherein said curing step comprisesexposing the coated compressed core to a temperature in the range of40-70° C. for a period of time of at least 1 hour.
 67. The sustainedrelease tablet of any of claims 1-36, wherein the release of the4-aminopyridine, upon subjecting the tablet to an in vitro dissolutiontest employing 50 mM Phosphate Buffer, pH 6.8 as dissolution medium, isas follows: within the first 2 hours after the start of the test at most20% w/w of the total amount of the 4-aminopyridine contained in thesustained release tablet is released.
 68. The sustained release tabletof claim 67, wherein the release of the 4-aminopyridine is as follows:within the first 24 hours after the start of the test at least 80% w/wof the total amount of the 4-aminopyridine contained in the sustainedrelease tablet is released.